TY  - JOUR
AB  - Although the therapeutic potential of miRNA-mediated gene regulation has been investigated, its precise functional regulatory mechanism in neuropathic pain remains incompletely understood. In this study, we elucidate that miR-216a-3p serves as a critical non-coding RNA involved in the modulation of trigeminal-mediated neuropathic pain. By conducting RNA-seq and qPCR analysis, we observed a notable decrease of miR-216a-3p in the injured trigeminal ganglia (TG) of male rats. Intra-TG administration of miR-216a-3p agomir or lentiviral-mediated overexpression of miR-216a-3p specifically in sensory neurons of injured TGs alleviated established neuropathic pain behaviors, while downregulation of miR-216a-3p (pharmacologically or genetically) in naïve rats induced pain behaviors. Moreover, nerve injury significantly elevated the H3K27 trimethylation (H3K27me3) levels in the ipsilateral TG, thereby suppressing the SRY-box transcription factor 10 (SOX10) binding to the miR-216a-3p promoter and resulting in the reduction of miR-216a-3p. Inhibiting the enzymes that responsible for catalyzing H3K27me3 restored the nerve injury-induced reduction in miR-216a-3p expression and markedly ameliorated neuropathic pain behaviors. Furthermore, miR-216a-3p targeted stromal interaction molecule 1 (STIM1), and the decreased miR-216a-3p associated with neuropathic pain caused a significant upregulation in the protein abundance of STIM1. Conversely, overexpression of miR-216a-3p in the injured TG suppressed the upregulation of STIM1 expression and reversed the mechanical allodynia. Together, the mechanistic understanding of H3K27me3-dependent SOX10/miR-216a-3p/STIM1 signaling axial in sensory neurons may facilitate the discovery of innovative therapeutic strategies for neuropathic pain management.Significance Statement miRNAs are posttranscriptional regulators of gene expression that play critical roles in the pathogenesis of neuropathic pain. However, the detailed mechanisms by which most pain-associated miRNAs operate and their therapeutic potential are incompletely understood. Our present study revealed that nerve injury-induced trimethylation of lysine 27 on histone H3 (H3K27me3) reduces the binding of SOX10, a transcription factor, to the promoter region of the miR-216a-3p gene, leading to decreased expression of the microRNA, miR-216a-3p. This reduction subsequently promotes neuropathic pain by regulating STIM1. Given that miRNA-mediated gene regulation is a proposed therapeutic approach for treating neuropathic pain, our findings suggest that replenishing miR-216a-3p could serve as a novel strategy for treating chronic neuropathic pain.
AU  - Sun, Y.*
AU  - Tao, Y.*
AU  - Cao, J.*
AU  - Zhang, Y.*
AU  - Huang, Z.*
AU  - Wang, S.*
AU  - Lu, W.*
AU  - Zhu, Q.*
AU  - Shan, L.*
AU  - Jiang, D.
AU  - Tao, J.*
C1  - 72547
C2  - 56619
CY  - 11 Dupont Circle, Nw, Ste 500, Washington, Dc 20036 Usa
TI  - H3K27 trimethylation-mediated downregulation of miR-216a-3p in sensory neurons regulates neuropathic pain behaviors via targeting STIM1.
JO  - J. Neurosci.
VL  - 45
IS  - 1
PB  - Soc Neuroscience
PY  - 2025
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - During early development, memory systems gradually mature over time, in parallel with the gradual accumulation of knowledge. Yet, it is unknown whether and to what extent maturation is driven by discrete experience. Sleep is thought to contribute to the formation of long-term memory and knowledge through a systems consolidation process that is driven by specific sleep oscillations (i.e., ripples, spindles, and slow oscillations) in cortical and hippocampal networks. Based on these oscillatory signatures, we show here in rats that discrete spatial experience speeds the functional maturation of spatial memory systems during development. Juvenile male rats were exposed for 5 min periods to changes in the spatial configuration of two identical objects on postnatal day (PD)25, PD27, and PD29 (Spatial experience group), while a Control group was exposed on these occasions to the same two objects without changing their positions. On PD31, both groups were tested on a classical Object Place Recognition (OPR) task with a 3 h retention interval during which the sleep-associated EEG and hippocampal local field potentials were recorded. On PD31, consistent with forgoing studies, Control rats still did not express OPR memory. By contrast, rats with Spatial experience formed significant OPR memory and, in parallel, displayed an increased percentage of hippocampal ripples coupled to parietal slow oscillation-spindle complexes, and a stronger ripple-spindle phase-locking during the retention sleep. Our findings support the idea that experience promotes the maturation of memory systems during development by enhancing cortico-hippocampal information exchange and the formation of integrated knowledge representations during sleep.SIGNIFICANCE STATEMENT Cognitive and memory capabilities mature early in life. We show here that and how discrete spatial experience contributes to this process. Using a simple recognition paradigm in developing rats, we found that exposure of the rat pups to three short-lasting experiences enhances spatial memory capabilities to adult-like levels. The adult-like capability of building spatial memory was connected to a more precise coupling of ripples in the hippocampus with slow oscillation-spindle complexes in the thalamo-cortical system when the memory was formed during sleep. Our findings support the view that discrete experience accelerates maturation of cognitive and memory capabilities by enhancing the dialogue between hippocampus and cortex when these experiences are reprocessed during sleep.
AU  - Contreras, M.P.*
AU  - Fechner, J.*
AU  - Born, J.
AU  - Inostroza, M.*
C1  - 67714
C2  - 54022
CY  - 11 Dupont Circle, Nw, Ste 500, Washington, Dc 20036 Usa
SP  - 3509-3519
TI  - Accelerating maturation of spatial memory systems by experience – evidence from sleep oscillation signatures of memory processing.
JO  - J. Neurosci.
VL  - 43
IS  - 19
PB  - Soc Neuroscience
PY  - 2023
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen α3 (VI) (COL6A3) C-terminal domain (CTD). These Col6a3 CTT mice showed a recessive dystonia-like phenotype in both sexes. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3 CTT mice of both sexes have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3 CTT mice of both sexes was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control.SIGNIFICANCE STATEMENTDystonia is a movement disorder characterized by involuntary movements. We previously identified genetic variants affecting a specific domain of the COL6A3 protein as a cause of dystonia. Here, we created mice lacking the affected domain and observed an analogous movement disorder. Using a protein interaction screen, we found that the affected COL6A3 domain mediates an interaction with the cannabinoid receptor CB1R. Concordantly, our COL6A3-deficient mice showed a deficit in synaptic plasticity linked to a deficit in cannabinoid signaling. Pharmacological cannabinoid augmentation rescued the motor impairment of the mice. Thus, cannabinoid augmentation could be a promising avenue for treating dystonia, and we have identified a possible molecular mechanism mediating this.
AU  - Lam, D.D.
AU  - Williams, R.H.
AU  - Lujan, E.*
AU  - Tanabe, K.*
AU  - Huber, G.
AU  - Saw, N.L.*
AU  - Merl-Pham, J.
AU  - Salminen, A.V.
AU  - Lohse, D.
AU  - Spendiff, S.*
AU  - Plastini, M.J.*
AU  - Zech, M.
AU  - Lochmüller, H.*
AU  - Geerlof, A.
AU  - Hauck, S.M.
AU  - Shamloo, M.*
AU  - Wernig, M.*
AU  - Winkelmann, J.
C1  - 64024
C2  - 51673
CY  - 11 Dupont Circle, Nw, Ste 500, Washington, Dc 20036 Usa
SP  - 1557-1573
TI  - Collagen VI regulates motor circuit plasticity and motor performance by cannabinoid modulation.
JO  - J. Neurosci.
VL  - 42
IS  - 8
PB  - Soc Neuroscience
PY  - 2022
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Sleep shapes cortical network activity, fostering global homeostatic down-regulation of excitability while maintaining or even up-regulating excitability in selected networks in a manner that supports memory consolidation. Here we used two-photon calcium imaging of cortical layer 2/3 neurons in sleeping male mice to examine how these seemingly opposing dynamics are balanced in cortical networks. During slow-wave sleep (SWS) episodes, mean calcium activity of excitatory pyramidal (Pyr) cells decreased. Simultaneously, however, variance in Pyr population calcium activity increased, contradicting the notion of a homogenous down-regulation of network activity. Indeed, we identified a subpopulation of Pyr cells distinctly up-regulating calcium activity during SWS, which were highly active during sleep spindles known to support mnemonic processing. REM episodes following SWS were associated with a general down-regulation of Pyr cells - including the subpopulation of Pyr cells active during spindles - which persisted into following stages of sleep and wakefulness. Parvalbumin-positive inhibitory interneurons (PV-In) showed an increase in calcium activity during SWS episodes, while activity remained unchanged during REM sleep episodes. This supports the view that down-regulation of Pyr calcium activity during SWS results from increased somatic inhibition via PV-In, whereas down-regulation during REM sleep is achieved independently of such inhibitory activity. Overall, our findings show that SWS enables up-regulation of select cortical circuits (likely those which were involved in mnemonic processing) through a spindle-related process, whereas REM sleep mediates general down-regulation, possibly through synaptic re-normalization.SIGNIFICANCE STATEMENTSleep is thought to globally down-regulate cortical excitability and, concurrently, to up-regulate synaptic connections in neuron ensembles with newly encoded memory, with up-regulation representing a function of sleep spindles. Using in-vivo two-photon calcium imaging in combination with surface EEG recordings, we classified cells based on their calcium activity during sleep spindles. Spindle-active pyramidal cells persistently increased calcium activity during slow wave sleep (SWS) episodes while spindle-inactive cells decreased calcium activity. Subsequent rapid-eye movement (REM) sleep episodes profoundly reduced calcium activity in both cell clusters. Results indicate that SWS allows for a spindle-related differential up-regulation of ensembles whereas REM sleep functions to globally down-regulate networks.
AU  - Niethard, N.*
AU  - Brodt, S.*
AU  - Born, J.
C1  - 61788
C2  - 50459
CY  - 11 Dupont Circle, Nw, Ste 500, Washington, Dc 20036 Usa
SP  - 4212-4222
TI  - Cell-type specific dynamics of calcium activity in cortical circuits over the course of slow wave sleep and rapid eye movement sleep.
JO  - J. Neurosci.
VL  - 41
IS  - 19
PB  - Soc Neuroscience
PY  - 2021
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Narcolepsy, characterized by excessive daytime sleepiness, is associated with dysfunction of the hypothalamic hypocretin/orexin (Hcrt) system, either due to extensive loss of Hcrt cells (Type 1, NT1) or hypothesized Hcrt signaling impairment (Type 2, NT2). Accordingly, efforts to recapitulate narcolepsy-like symptoms in mice have involved ablating these cells or interrupting Hcrt signaling. Here, we describe orexin/Arch mice, in which a modified archaerhodopsin-3 gene was inserted downstream of the prepro-orexin promoter, resulting in expression of the yellow light-sensitive Arch-3 proton pump specifically within Hcrt neurons. Histological examination along with ex vivo and in vivo electrophysiological recordings of male and female orexin/Arch mice demonstrated silencing of Hcrt neurons when these cells were photoilluminated. However, high expression of the Arch transgene affected cellular and physiological parameters independent of photoillumination. The excitability of Hcrt neurons was reduced, and both circadian and metabolic parameters were perturbed in a subset of orexin/Arch mice that exhibited high levels of Arch expression. Orexin/Arch mice also had increased REM sleep under baseline conditions but did not exhibit cataplexy, a sudden loss of muscle tone during wakefulness characteristic of NT1. These aberrations resembled some aspects of mouse models with Hcrt neuron ablation, yet the number of Hcrt neurons in orexin/Arch mice was not reduced. Thus, orexin/Arch mice may be useful to investigate Hcrt system dysfunction when these neurons are intact, as is thought to occur in narcolepsy without cataplexy (NT2). These results also demonstrate the utility of extended phenotypic screening of transgenic models when specific neural circuits have been manipulated.SIGNIFICANCE STATEMENT Optogenetics has become an invaluable tool for functional dissection of neural circuitry. While opsin expression is often achieved by viral injection, stably integrated transgenes offer some practical advantages. Here, we demonstrate successful transgenic expression of an inhibitory opsin in hypocretin/orexin neurons, which are thought to promote or maintain wakefulness. Both brief and prolonged illumination resulted in inhibition of these neurons and induced sleep. However, even in the absence of illumination, these cells exhibited altered electrical characteristics, particularly when transgene expression was high. These aberrant properties affected metabolism and sleep, resulting in a phenotype reminiscent of the narcolepsy Type 2, a sleep disorder for which no good animal model currently exists.
AU  - Williams, R.H.
AU  - Tsunematsu, T.*
AU  - Thomas, A.M.*
AU  - Bogyo, K.*
AU  - Yamanaka, A.*
AU  - Kilduff, T.S.*
C1  - 57148
C2  - 47567
CY  - 11 Dupont Circle, Nw, Ste 500, Washington, Dc 20036 Usa
SP  - 9435-9452
TI  - Transgenic archaerhodopsin-3 expression in hypocretin/orexin neurons engenders cellular dysfunction and features of type 2 narcolepsy.
JO  - J. Neurosci.
VL  - 39
IS  - 47
PB  - Soc Neuroscience
PY  - 2019
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - A single nucleotide polymorphism substitution from glutamine (Gln, Q) to arginine (Arg, R) at codon 460 of the purinergic P2X7 receptor (P2X7R) has repeatedly been associated with mood disorders. The P2X7R-Gln460Arg variant per se is not compromised in its function. However, heterologous expression of P2X7R-Gln460Arg together with wild-type P2X7R has recently been demonstrated to impair receptor function. Here we show that this also applies to humanized mice coexpressing both human P2X7R variants. Primary hippocampal cells derived from heterozygous mice showed an attenuated calcium uptake upon agonist stimulation. While humanized mice were unaffected in their behavioral repertoire under basal housing conditions, mice that harbor both P2X7R variants showed alterations in their sleep quality resembling signs of a prodromal disease stage. Also healthy heterozygous human subjects showed mild changes in sleep parameters. These results indicate that heterozygosity for the wild-type P2X7R and its mood disorder-associated variant P2X7R-Gln460Arg represents a genetic risk factor, which is potentially able to convey susceptibility to mood disorders.
AU  - Metzger, M.W.*
AU  - Walser, S.M.*
AU  - Dedic, N.*
AU  - Aprile-Garcia, F.*
AU  - Jakubcakova, V.*
AU  - Adamczyk, M.*
AU  - Webb, K.J.*
AU  - Uhr, M.*
AU  - Refojo, D.*
AU  - Schmidt, M.V.*
AU  - Friess, E.*
AU  - Steiger, A.*
AU  - Kimura, M.*
AU  - Chen, A.*
AU  - Holsboer, F.*
AU  - Arzt, E.*
AU  - Wurst, W.
AU  - Deussing, J.M.*
C1  - 52545
C2  - 44066
CY  - Washington
SP  - 11688-11700
TI  - Heterozygosity for the mood disorder-associated variant Gln460Arg alters P2X7 receptor function and sleep quality.
JO  - J. Neurosci.
VL  - 37
IS  - 48
PB  - Soc Neuroscience
PY  - 2017
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Neurons and glial cells exchange energy-rich metabolites and it has been suggested, originally based on in vitro data, that astrocytes provide lactate to glutamatergic synapses ("lactate shuttle"). Here, we have studied astrocytes that lack mitochondrial respiration in vitro and in vivo A novel mouse mutant (GLAST(CreERT2):Cox10(flox/flox) ) was generated, in which the administration of tamoxifen causes mutant astrocytes to fail in the assembly of mitochondrial cytochrome c oxidase (COX). Focussing on cerebellar Bergmann glial cells that exhibit the highest rate of Cre-mediated recombination, we find a normal density of viable astrocytes even one year after tamoxifen-induced Cox10 gene targeting. Our data show that Bergmann glial cells, and presumably all astrocytes, can survive by aerobic glycolysis for an extended period of time, in the absence of glial pathology or unspecific signs of neurodegeneration.SIGNIFICANCE STATEMENTWhen astrocytes are placed into culture they import glucose and release lactate, an energy-rich metabolite readily metabolized by neurons. This observation led to the "glia-to-neuron lactate shuttle hypothesis", but in vivo evidence for this hypothesis is weak. To study astroglial energy metabolism and the directionality of lactate flux, we generated conditional Cox10 mouse mutants lacking mitochondrial respiration in astrocytes thus forcing these cells to survive by aerobic glycolysis. Here, we report that these mice are fully viable in the absence of any signs of glial or neuronal loss, suggesting that astrocytes are naturally glycolytic cells.
AU  - Supplie, L.M.*
AU  - Düking, T.*
AU  - Campbell, G.*
AU  - Díaz, F.*
AU  - Moraes, C.T.*
AU  - Götz, M.
AU  - Hamprecht, B.*
AU  - Boretius, S.*
AU  - Mahad, D.*
AU  - Nave, K.A.*
C1  - 50754
C2  - 42513
CY  - Washington
SP  - 4231-4242
TI  - Respiration-deficient astrocytes survive as glycolytic cells in vivo.
JO  - J. Neurosci.
VL  - 37
IS  - 16
PB  - Soc Neuroscience
PY  - 2017
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Wingless-related MMTV integration site 1 (WNT1)/β-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons, including the substantia nigra pars compacta (SNc) subpopulation that preferentially degenerates in Parkinson's disease (PD). However, the precise functions of WNT1/β-catenin signaling in this context remain unknown. Stem cell-based regenerative (transplantation) therapies for PD have not been implemented widely in the clinical context, among other reasons because of the heterogeneity and incomplete differentiation of the transplanted cells. This might result in tumor formation and poor integration of the transplanted cells into the dopaminergic circuitry of the brain. Dickkopf 3 (DKK3) is a secreted glycoprotein implicated in the modulation of WNT/β-catenin signaling. Using mutant mice, primary ventral midbrain cells, and pluripotent stem cells, we show that DKK3 is necessary and sufficient for the correct differentiation of a rostrolateral mdDA neuron subset. Dkk3 transcription in the murine ventral midbrain coincides with the onset of mdDA neurogenesis and is required for the activation and/or maintenance of LMX1A (LIM homeobox transcription factor 1α) and PITX3 (paired-like homeodomain transcription factor 3) expression in the corresponding mdDA precursor subset, without affecting the proliferation or specification of their progenitors. Notably, the treatment of differentiating pluripotent stem cells with recombinant DKK3 and WNT1 proteins also increases the proportion of mdDA neurons with molecular SNc DA cell characteristics in these cultures. The specific effects of DKK3 on the differentiation of rostrolateral mdDA neurons in the murine ventral midbrain, together with its known prosurvival and anti-tumorigenic properties, make it a good candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD. SIGNIFICANCE STATEMENT: We show here that Dickkopf 3 (DKK3), a secreted modulator of WNT (Wingless-related MMTV integration site)/β-catenin signaling, is both necessary and sufficient for the proper differentiation and survival of a rostrolateral (parabrachial pigmented nucleus and dorsomedial substantia nigra pars compacta) mesodiencephalic dopaminergic neuron subset, using Dkk3 mutant mice and murine primary ventral midbrain and pluripotent stem cells. The progressive loss of these dopamine-producing mesodiencephalic neurons is a hallmark of human Parkinson's disease, which can up to now not be halted by clinical treatments of this disease. Thus, the soluble DKK3 protein might be a promising new agent for the improvement of current protocols for the directed differentiation of pluripotent and multipotent stem cells into mesodiencephalic dopaminergic neurons and for the promotion of their survival in situ.
AU  - Fukusumi, Y.
AU  - Meier, F.
AU  - Götz, S.
AU  - Matheus, F.
AU  - Irmler, M.
AU  - Beckervordersandforth, R.*
AU  - Faus-Kessler, T.
AU  - Minina, E.
AU  - Rauser, B.
AU  - Zhang, J.
AU  - Arenas, E.*
AU  - Andersson, E.A.*
AU  - Niehrs, C.*
AU  - Beckers, J.
AU  - Simeone, A.*
AU  - Wurst, W.
AU  - Prakash, N.
C1  - 46906
C2  - 39028
SP  - 13385-13401
TI  - Dickkopf3 promotes the differentiation of a rostrolateral midbrain dopaminergic neuronal subset in vivo and from pluripotent stem cells in vitro in the mouse.
JO  - J. Neurosci.
VL  - 35
IS  - 39
PY  - 2015
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Sleep supports the consolidation of motor sequence memories, yet it remains unclear whether sleep stabilizes or actually enhances motor sequence performance. Here we assessed the time course of motor memory consolidation in humans, taking early boosts in performance into account and varying the time between training and sleep. Two groups of subjects, each participating in a short wake condition and a longer sleep condition, were trained on the sequential finger-tapping task in the evening and were tested (1) after wake intervals of either 30 min or 4 h and (2) after a night of sleep that ensued either 30 min or 4 h after training. The results show an early boost in performance 30 min after training and a subsequent decay across the 4 h wake interval. When sleep followed 30 min after training, post-sleep performance was stabilized at the early boost level. Sleep at 4 h after training restored performance to the early boost level, such that, 12 h after training, performance was comparable regardless of whether sleep occurred 30 min or 4 h after training. These findings indicate that sleep does not enhance but rather stabilizes motor sequence performance without producing additional gains.
AU  - Nettersheim, A.*
AU  - Hallschmid, M.
AU  - Born, J.
AU  - Diekelmann, S.*
C1  - 44570
C2  - 37005
CY  - Washington
SP  - 6696-6702
TI  - The role of sleep in motor sequence consolidation: Stabilization rather than enhancement.
JO  - J. Neurosci.
VL  - 35
IS  - 17
PB  - Soc Neuroscience
PY  - 2015
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Deposition of aggregated amyloid-β (Aβ) peptide in brain is an early event and hallmark pathology of Alzheimer's disease and cerebral Aβ angiopathy. Experimental evidence supports the concept that Aβ multimers can act as seeds and structurally corrupt other Aβ peptides by a self-propagating mechanism. Here we compare the induction of cerebral β-amyloidosis by intraperitoneal applications of Aβ-containing brain extracts in three Aβ-precursor protein (APP) transgenic mouse lines that differ in levels of transgene expression in brain and periphery (APP23 mice, APP23 mice lacking murine APP, and R1.40 mice). Results revealed that beta-amyloidosis induction, which could be blocked with an anti-Aβ antibody, was dependent on the amount of inoculated brain extract and on the level of APP/Aβ expression in the brain but not in the periphery. The induced Aβ deposits in brain occurred in a characteristic pattern consistent with the entry of Aβ seeds at multiple brain locations. Intraperitoneally injected Aβ could be detected in blood monocytes and some peripheral tissues (liver, spleen) up to 30 d after the injection but escaped histological and biochemical detection thereafter. These results suggest that intraperitoneally inoculated Aβ seeds are transported from the periphery to the brain in which corruptive templating of host Aβ occurs at multiple sites, most efficiently in regions with high availability of soluble Aβ.
AU  - Eisele, Y.S.*
AU  - Fritschi, S.K.*
AU  - Hamaguchi, T.*
AU  - Obermüller, U.*
AU  - Füger, P.*
AU  - Skodras, A.*
AU  - Schäfer, C.*
AU  - Odenthal, J.*
AU  - Heikenwälder, M.
AU  - Staufenbiel, M.*
AU  - Jucker, M.*
C1  - 31855
C2  - 34837
CY  - Washington
SP  - 10264-10273
TI  - Multiple factors contribute to the peripheral induction of cerebral β-amyloidosis.
JO  - J. Neurosci.
VL  - 34
IS  - 31
PB  - Soc Neuroscience
PY  - 2014
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Inherited mutations that lead to misfolding of the visual pigment rhodopsin (Rho) are a prominent cause of photoreceptor neuron (PN) degeneration and blindness. How Rho proteotoxic stress progressively impairs PN viability remains unknown. To identify the pathways that mediate Rho toxicity in PNs, we performed a comprehensive proteomic profiling of retinas from Drosophila transgenics expressing Rh1(P37H), the equivalent of mammalian Rho(P23H), the most common Rho mutation linked to blindness in humans. Profiling of young Rh1(P37H) retinas revealed a coordinated upregulation of energy-producing pathways and attenuation of energy-consuming pathways involving target of rapamycin (TOR) signaling, which was reversed in older retinas at the onset of PN degeneration. We probed the relevance of these metabolic changes to PN survival by using a combination of pharmacological and genetic approaches. Chronic suppression of TOR signaling, using the inhibitor rapamycin, strongly mitigated PN degeneration, indicating that TOR signaling activation by chronic Rh1(P37H) proteotoxic stress is deleterious for PNs. Genetic inactivation of the endoplasmic reticulum stress-induced JNK/TRAF1 axis as well as the APAF-1/caspase-9 axis, activated by damaged mitochondria, dramatically suppressed Rh1(P37H)-induced PN degeneration, identifying the mitochondria as novel mediators of Rh1(P37H) toxicity. We thus propose that chronic Rh1(P37H) proteotoxic stress distorts the energetic profile of PNs leading to metabolic imbalance, mitochondrial failure, and PN degeneration and therapies normalizing metabolic function might be used to alleviate Rh1(P37H) toxicity in the retina. Our study offers a glimpse into the intricate higher order interactions that underlie PN dysfunction and provides a useful resource for identifying other molecular networks that mediate Rho toxicity in PNs.
AU  - Griciuc, A.
AU  - Roux, M.J.*
AU  - Merl, J.
AU  - Giangrande, A.*
AU  - Hauck, S.M.
AU  - Aron, L.*
AU  - Ueffing, M.
C1  - 30623
C2  - 33765
CY  - Washington
SP  - 2797-2812
TI  - Proteomic survey reveals altered energetic patterns and metabolic failure prior to retinal degeneration.
JO  - J. Neurosci.
VL  - 34
IS  - 8
PB  - Soc Neuroscience
PY  - 2014
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Normal brain function requires balanced development of excitatory and inhibitory synapses. An imbalance in synaptic transmission underlies many brain disorders such as epilepsy, schizophrenia, and autism. Compared with excitatory synapses, relatively little is known about the molecular control of inhibitory synapse development. We used a genetic approach in mice to identify the Ig superfamily member IgSF9/Dasm1 as a candidate homophilic synaptic adhesion protein that regulates inhibitory synapse development. IgSF9 is expressed in pyramidal cells and subsets of interneurons in the CA1 region of hippocampus. Electrophysiological recordings of acute hippocampal slices revealed that genetic inactivation of the IgSF9 gene resulted in fewer functional inhibitory synapses; however, the strength of the remaining synapses was unaltered. These physiological abnormalities were correlated with decreased expression of inhibitory synapse markers in IgSF9.
AU  - Mishra, A.*
AU  - Traut, M.H.*
AU  - Becker, L.
AU  - Klopstock, T.
AU  - Stein, V.*
AU  - Klein, R.*
C1  - 30831
C2  - 33904
CY  - Washington
SP  - 4187-4199
TI  - Genetic evidence for the adhesion protein IgSF9/Dasm1 to regulate inhibitory synapse development independent of its intracellular domain.
JO  - J. Neurosci.
VL  - 34
IS  - 12
PB  - Soc Neuroscience
PY  - 2014
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise-a strong modifier of adult hippocampal neurogenesis-accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesis-dependent hippocampal plasticity.
AU  - Steib, K.
AU  - Schäffner, I.
AU  - Jagasia, R.
AU  - Ebert, B.
AU  - Lie, D.C.
C1  - 31250
C2  - 34249
CY  - Washington
SP  - 6624-6633
TI  - Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain.
JO  - J. Neurosci.
VL  - 34
IS  - 19
PB  - Soc Neuroscience
PY  - 2014
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - The role of neuronal noncoding RNAs in energy control of the body is not fully understood. The arcuate nucleus (ARC) of the hypothalamus comprises neurons regulating food intake and body weight. Here we show that Dicer-dependent loss of microRNAs in these neurons of adult (DicerCKO) mice causes chronic overactivation of the signaling pathways involving phosphatidylinositol-3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) and an imbalance in the levels of neuropeptides, resulting in severe hyperphagic obesity. Similarly, the activation of PI3K-Akt-mTOR pathway due to Pten deletion in the adult forebrain leads to comparable weight increase. Conversely, the mTORC1 inhibitor rapamycin normalizes obesity in mice with an inactivated Dicer1 or Pten gene. Importantly, the continuous delivery of oligonucleotides mimicking microRNAs, which are predicted to target PI3K-Akt-mTOR pathway components, to the hypothalamus attenuates adiposity in DicerCKO mice. Furthermore, loss of miR-103 causes strong upregulation of the PI3K-Akt-mTOR pathway in vitro and its application into the ARC of the Dicer-deficient mice both reverses upregulation of Pik3cg, the mRNA encoding the catalytic subunit p110γ of the PI3K complex, and attenuates the hyperphagic obesity. Our data demonstrate in vivo the crucial role of neuronal microRNAs in the control of energy homeostasis.
AU  - Vinnikov, I.A.*
AU  - Hajdukiewicz, K.*
AU  - Reymann, J.*
AU  - Beneke, J.*
AU  - Czajkowski, R.*
AU  - Roth, L.C.*
AU  - Novak, M.*
AU  - Roller, A.
AU  - Dörner, N.*
AU  - Starkuviene, V.*
AU  - Theis, F.J.
AU  - Erfle, H.*
AU  - Schütz, G.*
AU  - Grinevich, V.*
AU  - Konopka, W.*
C1  - 31885
C2  - 34840
CY  - Washington
SP  - 10659-10674
TI  - Hypothalamic miR-103 protects from hyperphagic obesity in mice.
JO  - J. Neurosci.
VL  - 34
IS  - 32
PB  - Soc Neuroscience
PY  - 2014
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Proteolytic shedding of cell surface proteins generates paracrine signals involved in numerous signaling pathways. Neuregulin 1 (NRG1) type III is involved in myelination of the peripheral nervous system, for which it requires proteolytic activation by proteases of the ADAM family and BACE1. These proteases are major therapeutic targets for the prevention of Alzheimer's disease because they are also involved in the proteolytic generation of the neurotoxic amyloid beta-peptide. Identification and functional investigation of their physiological substrates is therefore of greatest importance in preventing unwanted side effects. Here we investigated proteolytic processing of NRG1 type III and demonstrate that the ectodomain can be cleaved by three different sheddases, namely ADAM10, ADAM17, and BACE1. Surprisingly, we not only found cleavage by ADAM10, ADAM17, and BACE1 C-terminal to the epidermal growth factor (EGF)-like domain, which is believed to play a pivotal role in signaling, but also additional cleavage sites for ADAM17 and BACE1 N-terminal to that domain. Proteolytic processing at N- and C-terminal sites of the EGF-like domain results in the secretion of this domain from NRG1 type III. The soluble EGF-like domain is functionally active and stimulates ErbB3 signaling in tissue culture assays. Moreover, the soluble EGF-like domain is capable of rescuing hypomyelination in a zebrafish mutant lacking BACE1. Our data suggest that NRG1 type III-dependent myelination is not only controlled by membrane-retained NRG1 type III, but also in a paracrine manner via proteolytic liberation of the EGF-like domain.
AU  - Fleck, D.*
AU  - van Bebber, F.*
AU  - Colombo, A.*
AU  - Galante, C.*
AU  - Schwenk, B.M.*
AU  - Rabe, L.*
AU  - Hampel, H.*
AU  - Novak, B.*
AU  - Kremmer, E.
AU  - Tahirovic, S.*
AU  - Edbauer, D.*
AU  - Lichtenthaler, S.F.*
AU  - Schmid, B.*
AU  - Willem, M.*
AU  - Haass, C.*
C1  - 24720
C2  - 31655
SP  - 7856-7869
TI  - Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling.
JO  - J. Neurosci.
VL  - 33
IS  - 18
PB  - Soc. Neuroscience
PY  - 2013
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Neural stem cells (NSCs) generate new hippocampal dentate granule neurons throughout adulthood. The genetic programs controlling neuronal differentiation of adult NSCs are only poorly understood. Here we show that, in the adult mouse hippocampus, expression of the SoxC transcription factors Sox4 and Sox11 is initiated around the time of neuronal commitment of adult NSCs and is maintained in immature neurons. Overexpression of Sox4 and Sox11 strongly promotes in vitro neurogenesis from adult NSCs, whereas ablation of Sox4/Sox11 prevents in vitro and in vivo neurogenesis from adult NSCs. Moreover, we demonstrate that SoxC transcription factors target the promoters of genes that are induced on neuronal differentiation of adult NSCs. Finally, we show that reprogramming of astroglia into neurons is dependent on the presence of SoxC factors. These data identify SoxC proteins as essential contributors to the genetic network controlling neuronal differentiation in adult neurogenesis and neuronal reprogramming of somatic cells.
AU  - Mu, L.
AU  - Berti, L.
AU  - Masserdotti, G.
AU  - Covic, M.
AU  - Michaelidis, T.M.
AU  - Doberauer, K.
AU  - Merz, K.
AU  - Rehfeld, F.
AU  - Haslinger, A.
AU  - Wegner, M.*
AU  - Sock, E.*
AU  - Lefebvre, V.*
AU  - Couillard-Despres, S.*
AU  - Aigner, L.*
AU  - Berninger, B.
AU  - Lie, D.C.
C1  - 7262
C2  - 29784
SP  - 3067-3080
TI  - SoxC transcription factors are required for neuronal differentiation in adult hippocampal neurogenesis.
JO  - J. Neurosci.
VL  - 32
IS  - 9
PB  - Society for Neuroscience
PY  - 2012
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - MicroRNAs have emerged as key posttranscriptional regulators of gene expression during vertebrate development. We show that the miR-200 family plays a crucial role for the proper generation and survival of ventral neuronal populations in the murine midbrain/hindbrain region, including midbrain dopaminergic neurons, by directly targeting the pluripotency factor Sox2 and the cell-cycle regulator E2F3 in neural stem/progenitor cells. The lack of a negative regulation of Sox2 and E2F3 by miR-200 in conditional Dicer1 mutants (En1(+/Cre); Dicer1(flox/flox) mice) and after miR-200 knockdown in vitro leads to a strongly reduced cell-cycle exit and neuronal differentiation of ventral midbrain/hindbrain (vMH) neural progenitors, whereas the opposite effect is seen after miR-200 overexpression in primary vMH cells. Expression of miR-200 is in turn directly regulated by Sox2 and E2F3, thereby establishing a unilateral negative feedback loop required for the cell-cycle exit and neuronal differentiation of neural stem/progenitor cells. Our findings suggest that the posttranscriptional regulation of Sox2 and E2F3 by miR-200 family members might be a general mechanism to control the transition from a pluripotent/multipotent stem/progenitor cell to a postmitotic and more differentiated cell.
AU  - Peng, C.
AU  - Li, N.*
AU  - Ng, Y.K.
AU  - Zhang, J.
AU  - Meier, F.
AU  - Theis, F.J.
AU  - Merkenschlager, M.*
AU  - Chen, W.*
AU  - Wurst, W.
AU  - Prakash, N.
C1  - 8586
C2  - 30192
SP  - 13292-13308
TI  - A unilateral negative feedback loop between miR-200 microRNAs and Sox2/E2F3 controls neural progenitor cell-cycle exit and differentiation.
JO  - J. Neurosci.
VL  - 32
IS  - 38
PB  - Society of Neuroscience
PY  - 2012
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Behavioral syndromes are suites of two or more behaviors that correlate across environmental contexts. The aggression-boldness syndrome links aggression, boldness, and exploratory activity in a novel environment. Although aggression-boldness has been described in many animals, the mechanism linking its behavioral components is not known. Here we show that mutation of the gene encoding fibroblast growth factor receptor 1a (fgfr1a) simultaneously increases aggression, boldness, and exploration in adult zebrafish. We demonstrate that altered Fgf signaling also results in reduced brain histamine levels in mutants. Pharmacological increase of histamine signaling is sufficient to rescue the behavioral phenotype of fgfr1a mutants. Together, we show that a single genetic locus can underlie the aggression-boldness behavioral syndrome. We also identify one of the neurotransmitter pathways that may mediate clustering of these behaviors.
AU  - Norton, W.H.J.
AU  - Stumpenhorst, K.
AU  - Faus-Kessler, T.
AU  - Folchert, A.
AU  - Rohner, N.*
AU  - Harris, M.P.*
AU  - Callebert, J.*
AU  - Bally-Cuif, L.
C1  - 6725
C2  - 29170
CY  - Washington, DC, USA
SP  - 13796-13807
TI  - Modulation of Fgfr1a signaling in zebrafish reveals a genetic basis for the aggression-boldness syndrome.
JO  - J. Neurosci.
VL  - 31
IS  - 39
PB  - Society for Neuroscience
PY  - 2011
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Pitx3 is a critical homeodomain transcription factor for the proper development and survival of mesodiencephalic dopaminergic (mdDA) neurons in mammals. Several variants of this gene have been associated with human Parkinson's disease (PD), and lack of Pitx3 in mice causes the preferential loss of substantia nigra pars compacta (SNc) mdDA neurons that are most affected in PD. It is currently unclear how Pitx3 activity promotes the survival of SNc mdDA neurons and which factors act upstream and downstream of Pitx3 in this context. Here we show that a transient expression of glial cell line-derived neurotrophic factor (GDNF) in the murine ventral midbrain (VM) induces transcription of Pitx3 via NF-κB-mediated signaling, and that Pitx3 is in turn required for activating the expression of brain-derived neurotrophic factor (BDNF) in a rostrolateral (SNc) mdDA neuron subpopulation during embryogenesis. The loss of BDNF expression correlates with the increased apoptotic cell death of this mdDA neuronal subpopulation in Pitx3(-/-) mice, whereas treatment of VM cell cultures with BDNF augments the survival of the Pitx3(-/-) mdDA neurons. Most importantly, only BDNF but not GDNF protects mdDA neurons against 6-hydroxydopamine-induced cell death in the absence of Pitx3. As the feedforward regulation of GDNF, Pitx3, and BDNF expression also persists in the adult rodent brain, our data suggest that the disruption of the regulatory interaction between these three factors contributes to the loss of mdDA neurons in Pitx3(-/-) mutant mice and perhaps also in human PD.
AU  - Peng, C.
AU  - Aron, L.*
AU  - Klein, R.*
AU  - Li, M.*
AU  - Wurst, W.
AU  - Prakash, N.
AU  - Le, W.*
C1  - 6492
C2  - 28788
SP  - 12802-12815
TI  - Pitx3 is a critical mediator of GDNF-induced BDNF expression in nigrostriatal dopaminergic neurons.
JO  - J. Neurosci.
VL  - 31
IS  - 36
PB  - Society for Neuroscience
PY  - 2011
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Mutations in leucine-rich repeat kinase 2 (LRRK2) are the single most common cause of inherited Parkinson's disease. Little is known about its involvement in the pathogenesis of Parkinson's disease mainly because of the lack of knowledge about the physiological role of LRRK2. To determine the function of LRRK2, we studied the impact of short hairpin RNA-mediated silencing of LRRK2 expression in cortical neurons. Paired recording indicated that LRRK2 silencing affects evoked postsynaptic currents. Furthermore, LRRK2 silencing induces at the presynaptic site a redistribution of vesicles within the bouton, altered recycling dynamics, and increased vesicle kinetics. Accordingly, LRRK2 protein is present in the synaptosomal compartment of cortical neurons in which it interacts with several proteins involved in vesicular recycling. Our results suggest that LRRK2 modulates synaptic vesicle trafficking and distribution in neurons and in consequence participates in regulating the dynamics between vesicle pools inside the presynaptic bouton.
AU  - Piccoli, G.
AU  - Condliffe, S.B.*
AU  - Bauer, M.
AU  - Giesert, F.
AU  - Boldt, K.
AU  - de Astis, S.*
AU  - Meixner, A.
AU  - Sarioglu, H.
AU  - Vogt Weisenhorn, D.M.
AU  - Wurst, W.
AU  - Gloeckner, C.J.
AU  - Matteoli, M.*
AU  - Sala, C.*
AU  - Ueffing, M.
C1  - 5025
C2  - 28710
SP  - 2225-2237
TI  - LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.
JO  - J. Neurosci.
VL  - 31
IS  - 6
PB  - Soc Neuroscience
PY  - 2011
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - It is generally suggested that astrocytes play important restorative functions after brain injury, yet little is known regarding their recruitment to sites of injury, despite numerous in vitro experiments investigating astrocyte polarity. Here, we genetically manipulated one of the proposed key signals, the small RhoGTPase Cdc42, selectively in mouse astrocytes in vitro and in vivo. We used an in vitro scratch assay as a minimal wounding model and found that astrocytes lacking Cdc42 (Cdc42Δ) were still able to form protrusions, although in a nonoriented way. Consequently, they failed to migrate in a directed manner toward the scratch. When animals were injured in vivo through a stab wound, Cdc42Δ astrocytes developed protrusions properly oriented toward the lesion, but the number of astrocytes recruited to the lesion site was significantly reduced. Surprisingly, however, lesions in Cdc42Δ animals, harboring fewer astrocytes contained significantly higher numbers of microglial cells than controls. These data suggest that impaired recruitment of astrocytes to sites of injury has a profound and unexpected effect on microglia recruitment.
AU  - Robel, S.
AU  - Bardehle, S.
AU  - Lepier, A.*
AU  - Brakebusch, C.*
AU  - Götz, M.
C1  - 6360
C2  - 29166
SP  - 12471-12482
TI  - Genetic deletion of Cdc42 reveals a crucial role for astrocyte recruitment to the injury site in vitro and in vivo.
JO  - J. Neurosci.
VL  - 31
IS  - 35
PB  - Soc Neuroscience
PY  - 2011
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF₁), in experimental models of early-life stress have suggested a role for this endogenous stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF₁ knock-out (CRF₁-CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF₁ in the long-lasting effects of early-life stress on learning and memory. Early-life stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF₁ deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in stressed mice. In addition, early-life stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF₁-CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by early-life stress are at least partly dependent on persistent forebrain CRF₁ signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of early-life adversity.
AU  - Wang, X.D.*
AU  - Rammes, G.*
AU  - Kraev, I.*
AU  - Wolf, M.*
AU  - Liebl, C.*
AU  - Scharf, S.H.*
AU  - Rice, C.J.*
AU  - Wurst, W.
AU  - Holsboer, F.*
AU  - Deussing, J.M.*
AU  - Baram, T.Z.*
AU  - Stewart, M.G.*
AU  - Müller, M.B.*
AU  - Schmidt, M.V.*
C1  - 5629
C2  - 29163
SP  - 13625-13634
TI  - Forebrain CRF1 modulates early-life stress-programmed cognitive deficits.
JO  - J. Neurosci.
VL  - 31
IS  - 38
PB  - Soc Neuroscience
PY  - 2011
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - The limited generation of neurons during adulthood is controlled by a balance between quiescence and recruitment of neural stem cells (NSCs). We use here the germinal zone of the zebrafish adult telencephalon to examine how the frequency of NSC divisions is regulated. We show, using several in vivo techniques, that progenitors transit back and forth between the quiescent and dividing state, according to varying levels of Notch activity: Notch induction drives progenitors into quiescence, whereas blocking Notch massively reinitiates NSC division and subsequent commitment toward becoming neurons. Notch activation appears predominantly triggered by newly recruited progenitors onto their neighbors, suggesting an involvement of Notch in a self-limiting mechanism, once neurogenesis is started. These results identify for the first time a lateral inhibition-like mechanism in the context of adult neurogenesis and suggest that the equilibrium between quiescence and neurogenesis in the adult brain is controlled by fluctuations of Notch activity, thereby regulating the amount of adult-born neurons.
AU  - Chapouton, P.
AU  - Skupien, P.
AU  - Hesl, B.
AU  - Coolen, M.
AU  - Moore, J.C.*
AU  - Madelaine, R.*
AU  - Kremmer, E.
AU  - Faus-Kessler, T.
AU  - Blader, P.*
AU  - Lawson, N.D.*
AU  - Bally-Cuif, L.
C1  - 5905
C2  - 27435
SP  - 7961-7974
TI  - Notch activity levels control the balance between quiescence and recruitment of adult neural stem cells.
JO  - J. Neurosci.
VL  - 30
IS  - 23
PB  - Society Neuroscience
PY  - 2010
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Urocortin 3 (UCN3) is strongly expressed in specific nuclei of the rodent brain, at sites distinct from those expressing urocortin 1 and urocortin 2, the other endogenous ligands of corticotropin-releasing hormone receptor type 2 (CRH-R2). To determine the physiological role of UCN3, we generated UCN3-deficient mice, in which the UCN3 open reading frame was replaced by a tau-lacZ reporter gene. By means of this reporter gene, the nucleus parabrachialis and the premammillary nucleus were identified as previously unknown sites of UCN3 expression. Additionally, the introduced reporter gene enabled the visualization of axonal projections of UCN3-expressing neurons from the superior paraolivary nucleus to the inferior colliculus and from the posterodorsal part of the medial amygdala to the principal nucleus of the bed nucleus of the stria terminalis, respectively. The examination of tau-lacZ reporter gene activity throughout the brain underscored a predominant expression of UCN3 in nuclei functionally connected to the accessory olfactory system. Male and female mice were comprehensively phenotyped but none of the applied tests provided indications for a role of UCN3 in the context of hypothalamic-pituitary-adrenocortical axis regulation, anxiety- or depression-related behavior. However, inspired by the prevalent expression throughout the accessory olfactory system, we identified alterations in social discrimination abilities of male and female UCN3 knock-out mice that were also present in male CRH-R2 knock-out mice. In conclusion, our results suggest a novel role for UCN3 and CRH-R2 related to the processing of social cues and to the establishment of social memories.
AU  - Deussing, J.M.*
AU  - Breu, J.*
AU  - Kühne, C.*
AU  - Kallnik, M.
AU  - Bunck, M.*
AU  - Glasl, L.
AU  - Yen, Y.C.*
AU  - Schmidt, M.V.*
AU  - Zurmühlen, R.*
AU  - Vogl, A.M.*
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Hölter, S.M.
AU  - Wotjak, C.T.*
AU  - Landgraf, R.*
AU  - Hrabě de Angelis, M.
AU  - Holsboer, F.*
AU  - Wurst, W.
C1  - 456
C2  - 27223
CY  - Washington
SP  - 9103-9116
TI  - Urocortin 3 modulates social discrimination abilities via corticotropin-releasing hormone receptor type 2.
JO  - J. Neurosci.
VL  - 30
IS  - 27
PB  - Soc. Neuroscience
PY  - 2010
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - The generation of new neurons from neural stem cells in the adult hippocampal dentate gyrus contributes to learning and mood regulation. To sustain hippocampal neurogenesis throughout life, maintenance of the neural stem cell pool has to be tightly controlled. We found that the Notch/RBPJκ-signaling pathway is highly active in neural stem cells of the adult mouse hippocampus. Conditional inactivation of RBPJκ in neural stem cells in vivo resulted in increased neuronal differentiation of neural stem cells in the adult hippocampus at an early time point and depletion of the Sox2-positive neural stem cell pool and suppression of hippocampal neurogenesis at a later time point. Moreover, RBPJκ-deficient neural stem cells displayed impaired self-renewal in vitro and loss of expression of the transcription factor Sox2. Interestingly, we found that Notch signaling increases Sox2 promoter activity and Sox2 expression in adult neural stem cells. In addition, activated Notch and RBPJκ were highly enriched on the Sox2 promoter in adult hippocampal neural stem cells, thus identifying Sox2 as a direct target of Notch/RBPJκ signaling. Finally, we found that overexpression of Sox2 can rescue the self-renewal defect in RBPJκ-deficient neural stem cells. These results identify RBPJκ-dependent pathways as essential regulators of adult neural stem cell maintenance and suggest that the actions of RBPJκ are, at least in part, mediated by control of Sox2 expression.
AU  - Ehm, O.K.H.
AU  - Göritz, C.*
AU  - Covic, M.
AU  - Schäffner, I.
AU  - Schwarz, T.J.
AU  - Karaca, E.
AU  - Kempkes, B.
AU  - Kremmer, E.
AU  - Pfrieger, F.W.*
AU  - Espinosa, L.*
AU  - Bigas, A.*
AU  - Giachino, C.*
AU  - Taylor, V.*
AU  - Frisen, J.*
AU  - Lie, D.C.
C1  - 5302
C2  - 27720
SP  - 13794-13807
TI  - RBPJκ-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus.
JO  - J. Neurosci.
VL  - 30
IS  - 41
PY  - 2010
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Dicer-dependent noncoding RNAs, including microRNAs (miRNAs), play an important role in a modulation of translation of mRNA transcripts necessary for differentiation in many cell types. In vivo experiments using cell type-specific Dicer1 gene inactivation in neurons showed its essential role for neuronal development and survival. However, little is known about the consequences of a loss of miRNAs in adult, fully differentiated neurons. To address this question, we used an inducible variant of the Cre recombinase (tamoxifen-inducible CreERT2) under control of Camk2a gene regulatory elements. After induction of Dicer1 gene deletion in adult mouse forebrain, we observed a progressive loss of a whole set of brain-specific miRNAs. Animals were tested in a battery of both aversively and appetitively motivated cognitive tasks, such as Morris water maze, IntelliCage system, or trace fear conditioning. Compatible with rather long half-life of miRNAs in hippocampal neurons, we observed an enhancement of memory strength of mutant mice 12 weeks after the Dicer1 gene mutation, before the onset of neurodegenerative process. In acute brain slices, immediately after high-frequency stimulation of the Schaffer collaterals, the efficacy at CA3-to-CA1 synapses was higher in mutant than in control mice, whereas long-term potentiation was comparable between genotypes. This phenotype was reflected at the subcellular and molecular level by the elongated filopodia-like shaped dendritic spines and an increased translation of synaptic plasticity-related proteins, such as BDNF and MMP-9 in mutant animals. The presented work shows miRNAs as key players in the learning and memory process of mammals.
AU  - Konopka, W.*
AU  - Kiryk, A.*
AU  - Novak, M.*
AU  - Herwerth, M.*
AU  - Parkitna, J.R.*
AU  - Wawrzyniak, M.*
AU  - Kowarsch, A.
AU  - Michaluk, P.*
AU  - Dzwonek, J.*
AU  - Arnsperger, T.*
AU  - Wilczynski, G.*
AU  - Merkenschlager, M.*
AU  - Theis, F.J.
AU  - Köhr, G.*
AU  - Kaczmarek, L.*
AU  - Schütz, G.*
C1  - 5501
C2  - 28145
SP  - 14835-14842
TI  - MicroRNA loss enhances learning and memory in mice.
JO  - J. Neurosci.
VL  - 30
IS  - 44
PB  - Soc Neuroscience
PY  - 2010
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Increased vulnerability to aversive experiences is one of the main risk factors for stress-related psychiatric disorders as major depression. However, the molecular bases of vulnerability, on the one hand, and stress resilience, on the other hand, are still not understood. Increasing clinical and preclinical evidence suggests a central involvement of the glutamatergic system in the pathogenesis of major depression. Using a mouse paradigm, modeling increased stress vulnerability and depression-like symptoms in a genetically diverse outbred strain, and we tested the hypothesis that differences in AMPA receptor function may be linked to individual variations in stress vulnerability. Vulnerable and resilient animals differed significantly in their dorsal hippocampal AMPA receptor expression and AMPA receptor binding. Treatment with an AMPA receptor potentiator during the stress exposure prevented the lasting effects of chronic social stress exposure on physiological, neuroendocrine, and behavioral parameters. In addition, spatial short-term memory, an AMPA receptor-dependent behavior, was found to be predictive of individual stress vulnerability and response to AMPA potentiator treatment. Finally, we provide evidence that genetic variations in the AMPA receptor subunit GluR1 are linked to the vulnerable phenotype. Therefore, we propose genetic variations in the AMPA receptor system to shape individual stress vulnerability. Those individual differences can be predicted by the assessment of short-term memory, thereby opening up the possibility for a specific treatment by enhancing AMPA receptor function.
AU  - Schmidt, M.V.*
AU  - Trümbach, D.
AU  - Weber, P.*
AU  - Wagner, K.*
AU  - Scharf, S.H.*
AU  - Liebl, C.*
AU  - Datson, N.*
AU  - Namendorf, C.*
AU  - Gerlach, T.
AU  - Kühne, C.*
AU  - Uhr, M.*
AU  - Deussing, J.M.*
AU  - Wurst, W.
AU  - Binder, E.B.*
AU  - Holsboer, F.*
AU  - Müller, M.B.
C1  - 6284
C2  - 27481
CY  - Washington DC
SP  - 16949-16958
TI  - Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus.
JO  - J. Neurosci.
VL  - 30
IS  - 50
PB  - Society for Neuroscience
PY  - 2010
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Survival and integration of new neurons in the hippocampal circuit are rate-limiting steps in adult hippocampal neurogenesis. Neuronal network activity is a major regulator of these processes, yet little is known about the respective downstream signaling pathways. Here, we investigate the role of cAMP response element-binding protein (CREB) signaling in adult hippocampal neurogenesis. CREB is activated in new granule neurons during a distinct developmental period. Loss of CREB function in a cell-autonomous manner impairs dendritic development, decreases the expression of the neurogenic transcription factor NeuroD and of the neuronal microtubule-associated protein, doublecortin (DCX), and compromises the survival of newborn neurons. In addition, GABA-mediated excitation regulates CREB activation at early developmental stages. Importantly, developmental defects after loss of GABA-mediated excitation can be compensated by enhanced CREB signaling. These results indicate that CREB signaling is a central pathway in adult hippocampal neurogenesis, regulating the development and survival of new hippocampal neurons downstream of GABA-mediated excitation.
AU  - Jagasia, R.
AU  - Steib, K.
AU  - Englberger, E.
AU  - Herold, S.
AU  - Faus-Kessler, T.
AU  - Saxe, M.*
AU  - Gage, F.H.*
AU  - Song, H.*
AU  - Lie, D.C.
C1  - 1493
C2  - 26934
SP  - 7966-7977
TI  - GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus.
JO  - J. Neurosci.
VL  - 29
IS  - 25
PB  - Society for Neuroscience
PY  - 2009
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.
AU  - Khan, M.A.
AU  - Berti, L.
C1  - 1390
C2  - 26739
SP  - 12369-12371
TI  - Alzheimer's disease affects progenitor cells through aberrant β-catenin signaling.
JO  - J. Neurosci.
VL  - 29
IS  - 40
PB  - Society for Neuroscience
PY  - 2009
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Adult neuronal precursors retain the remarkable capacity to migrate long distances from the posterior (subventricular zone) to the most anterior [olfactory bulb (OB)] parts of the brain. The knowledge about the mechanisms that keep neuronal precursors in the migratory stream and organize this long-distance migration is incomplete. Here we show that blood vessels precisely outline the migratory stream for new neurons in the adult mammalian forebrain. Real-time video imaging of cell migration in the acute slices demonstrate that neuronal precursors are retained in the migratory stream and guided into the OB by blood vessels that serve as a physical substrate for migrating neuroblasts. Our data suggest that endothelial cells of blood vessels synthesize brain-derived neurotrophic factor (BDNF) that fosters neuronal migration via p75NTR expressed on neuroblasts. Interestingly, GABA released from neuroblasts induces Ca(2+)-dependent insertion of high-affinity TrkB receptors on the plasma membrane of astrocytes that trap extracellular BDNF. We hypothesize that this renders BDNF unavailable for p75NTR-expressing migrating cells and leads to their entrance into the stationary period. Our findings provide new insights into the functional organization of substrates that facilitate the long-distance journey of adult neuronal precursors.
AU  - Snapyan, M.*
AU  - Lemasson, M.*
AU  - Brill, M.S.
AU  - Blais, M.*
AU  - Massouh, M.*
AU  - Ninkovic, J.
AU  - Gravel, C.*
AU  - Berthod, F.*
AU  - Götz, M.
AU  - Barker, P.A.*
AU  - Parent, A.*
AU  - Saghatelyan, A.*
C1  - 1577
C2  - 26570
SP  - 4172-4188
TI  - Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signaling.
JO  - J. Neurosci.
VL  - 29
IS  - 13
PB  - Society for Neuroscience
PY  - 2009
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3 ',3,5-triiodothyronine (T-3) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T-3 transporters become hyperthyroid, if they are exposed directly to the high plasma T-3. The majority of T-3 uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T-3 transporter classes. mRNAs encoding six T-3 transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.
AU  - Wirth, E.K.*
AU  - Roth, S.*
AU  - Blechschmidt, C.*
AU  - Hölter, S.M.
AU  - Becker, L.
AU  - Rácz, I.
AU  - Zimmer, A.*
AU  - Klopstock, T.*
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Wurst, W.
AU  - Naumann, T.*
AU  - Bräuer, A.*
AU  - Hrabě de Angelis, M.
AU  - Köhrle, J.*
AU  - Grüters, A.*
AU  - Schweizer, U.*
C1  - 1027
C2  - 26398
SP  - 9439-9449
TI  - Neuronal 3',3,5-triiodothyronine (T₃) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T₃ transporter mutated in Allan-Herndon-Dudley syndrome.
JO  - J. Neurosci.
VL  - 29
IS  - 30
PB  - Society for Neuroscience
PY  - 2009
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Distinct olfactory bulb (OB) interneurons are thought to become specified depending on from which of the different subregions lining the lateral ventricle wall they originate, but the role of region-specific transcription factors (TFs) in the generation of OB interneurons diversity is still poorly understood. Despite the crucial roles of the Dlx family of TFs for patterning and neurogenesis in the ventral telencephalon during embryonic development, their role in adult neurogenesis has not yet been addressed. Here we show that in the adult brain, Dlx 1 and Dlx2 are expressed in progenitors of the lateral but not the dorsal subependymal zone (SEZ), thus exhibiting a striking regional specificity. Using retroviral vectors to examine the function of Dlx2 in a cell-autonomous manner, we demonstrate that this TF is necessary for neurogenesis of virtually all OB interneurons arising from the lateral SEZ. Beyond its function in generic neurogenesis, Dlx2 also plays a crucial role in neuronal subtype specification in the OB, promoting specification of adult-born periglomerular neurons (PGNs) toward a dopaminergic fate. Strikingly, Dlx2 requires interaction with Pax6, because Pax6 deletion blocks Dlx2-mediated PGN specification. Thus, Dlx2 wields a dual function by first instructing generic neurogenesis from adult precursors and subsequently specifying PGN subtypes in conjunction with Pax6.
AU  - Brill, M.S.
AU  - Snapyan, M.*
AU  - Wohlfrom, H.
AU  - Ninkovic, J.
AU  - Jawerka, M.
AU  - Mastick, G.S.*
AU  - Ashery-Padan, R.*
AU  - Saghatelyan, A.*
AU  - Berninger, B.
AU  - Götz, M.
C1  - 1996
C2  - 25403
SP  - 6439-6452
TI  - A Dlx2- and Pax6-dependent transcriptional code for periglomerular neuron specification in the adult olfactory bulb.
JO  - J. Neurosci.
VL  - 28
IS  - 25
PB  - Society for Neuroscience
PY  - 2008
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - In the mammalian brain, neurogenesis continues only in few regions of the forebrain. The molecular signals governing neurogenesis in these unique neurogenic niches, however, are still ill defined. Here, we show that bone morphogenic protein (BMP)-mediated signaling is active in adult neural stem cells and is crucial to initiate the neurogenic lineage in the adult mouse subependymal zone. Conditional deletion of Smad4 in adult neural stem cells severely impairs neurogenesis, and this is phenocopied by infusion of Noggin, an extracellular antagonist of BMP. Smad4 deletion in stem, but not progenitor cells, as well as Noggin infusion lead to an increased number of Olig2-expressing progeny that migrate to the corpus callosum and differentiate into oligodendrocytes. Transplantation experiments further verified the cell-autonomous nature of this phenotype. Thus, BMP-mediated signaling via Smad4 is required to initiate neurogenesis from adult neural stem cells and suppress the alternative fate of oligodendrogliogenesis
AU  - Colak, D.
AU  - Mori, T.
AU  - Brill, M.S.
AU  - Pfeifer, A.*
AU  - Falk, S.*
AU  - Deng, C.*
AU  - Monteiro, R.*
AU  - Mummery, C.*
AU  - Sommer, L.*
AU  - Götz, M.
C1  - 441
C2  - 25400
SP  - 434-445
TI  - Adult neurogenesis requires Smad4-mediated bone morphogenic protein signaling in stem cells.
JO  - J. Neurosci.
VL  - 28
IS  - 2
PB  - Society for Neuroscience
PY  - 2008
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Despite their abundance, still little is known about the rather frequent, constantly proliferating progenitors spread throughout the adult mouse brain parenchyma. The majority of these progenitors express the basic-helix-loop-helix transcription factor Olig2, and their number further increases after injury. Here, we examine the progeny of this progenitor population by genetic fate mapping using tamoxifen-inducible Cre-recombination in the Olig2 locus to turn on permanent reporter gene expression in the adult brain. Consistent with Olig2 expression in proliferating NG2(+) progenitors, most reporter(+) cells seen shortly after initiating recombination at adult stages incorporated BrdU and contained the proteoglycan NG2 in both the gray (GM) and the white matter (WM) of the cerebral cortex. However, at longer time points after induction, we observed profound differences in the identity of reporter(+) cells in the WM and GM. Whereas most of the Olig2(+) progenitors had generated mature, myelinating oligodendrocytes in the WM, hardly any reporter(+) cells showing mature oligodendrocyte characteristics were detectable even up to 6 months after recombination in the GM. In the GM, most reporter(+) cells remained NG2(+), even after injury, but stopped proliferating rather soon after recombination. Thus, our results demonstrate the continuous generation of mature, myelinating oligodendrocytes in the WM, whereas cells in the GM generated mostly postmitotic NG2(+) glia.
AU  - Dimou, L.*
AU  - Simon, C.*
AU  - Kirchhoff, F.*
AU  - Takebayashi, H.*
AU  - Goetz, M.
C1  - 3190
C2  - 25858
SP  - 10434-10442
TI  - Progeny of Olig2-expressing progenitors in the gray and white matter of the adult mouse cerebral cortex.
JO  - J. Neurosci.
VL  - 28
IS  - 41
PB  - Society for Neuroscience
PY  - 2008
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - The homeobox-containing transcription factor Otx2 is crucially involved in fate determination of midbrain neurons. Mutant mice, in which Otx2 was conditionally inactivated by a Cre recombinase expressed under the transcriptional control of the Engrailed1 (En1) gene (En1(cre/+); Otx2(flox/flox)), show a reduced number of dopaminergic neurons and an increased number of serotonergic neurons in the ventral midbrain. Despite these developmental anatomical alterations, En1(cre/+); Otx2(flox/flox) adult mice display normal motor function. Here, we further investigated the neurological consequences of Otx2 inactivation in adult En1(cre/+); Otx2(flox/flox) mice. Adult En1(cre/+); Otx2(flox/flox) mice showed increased serotonin (5-HT) levels in the pons, ventral midbrain, hippocampus (CA3 subfield), and cerebral cortex, as indicated by HPLC and immunohistochemistry. Conversely, SERT (5-HT transporter) levels were decreased in conditional mutant brains. As a consequence of this increased 5-HT hyperinnervation, En1(cre/+); Otx2(flox/flox) mice were resistant to generalized seizures induced by the glutamate agonist kainic acid (KA). Indeed, prolonged pretreatment of En1(cre/+); Otx2(flox/flox) mice with the 5- HT synthesis inhibitor para- chlorophenylalanine (pCPA) restored brain 5-HT content to control levels, fully reestablishing KA seizure susceptibility. Accordingly, c- fos mRNA induction after KA was restricted to the hippocampus in En1(Cre/+); Otx2(flox/flox) mice, whereas a widespread c- fos mRNA labeling was observed throughout the brain of En1(Cre/+); Otx2(flox/flox) mice pretreated with pCPA. These results clearly show that increased brain 5- HT levels are responsible for seizure resistance in En1(cre/+); Otx2(flox/flox) mice and confirm the important role of 5-HT in the control of seizure spread.
AU  - Tripathi, P.P.*
AU  - di Giovannantonio, L.G.*
AU  - Viegi, A.*
AU  - Wurst, W.
AU  - Simeone, A.*
AU  - Bozzi, Y.*
C1  - 3666
C2  - 25896
SP  - 9271-9276
TI  - Serotonin hyperinnervation abolishes seizure susceptibility in Otx2 conditional mutant mice.
JO  - J. Neurosci.
VL  - 28
IS  - 37
PB  - Society for Neuroscience
PY  - 2008
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - With the exception of astroglia-like cells in the neurogenic niches of the telencephalic subependymal or hippocampal subgranular zone, astroglia in all other regions of the adult mouse brain do not normally generate neurons. Previous studies have shown, however, that early postnatal cortical astroglia in culture can be reprogrammed to adopt a neuronal fate after forced expression of Pax6, a transcription factor (TF) required for proper neuronal specification during embryonic corticogenesis. Here we show that also the proneural genes neurogenin-2 and Mash1 (mammalian achaete schute homolog 1) possess the ability to reprogram astroglial cells from early postnatal cerebral cortex. By means of time-lapse imaging of green fluorescent astroglia, we provide direct evidence that it is indeed cells with astroglial characteristics that give rise to neurons. Using patch-clamp recordings in culture, we show that astroglia-derived neurons acquire active conductances and are capable of firing action potentials, thus displaying hallmarks of true neurons. However, independent of the TF used for reprogramming, astroglia-derived neurons appear to mature more slowly compared with embryonic-born neurons and fail to generate a functional presynaptic output within the culturing period. However, when cocultured with embryonic cortical neurons, astroglia-derived neurons receive synaptic input, demonstrating that they are competent of establishing a functional postsynaptic compartment. Our data demonstrate that single TFs are capable of inducing a remarkable functional reprogramming of astroglia toward a truly neuronal identity.
AU  - Berninger, B.
AU  - Costa, M.R.
AU  - Koch, U.*
AU  - Schroeder, T.
AU  - Sutor, B.*
AU  - Grothe, B.*
AU  - Götz, M.
C1  - 2930
C2  - 24679
SP  - 8654-8664
TI  - Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia.
JO  - J. Neurosci.
VL  - 27
IS  - 32
PB  - Society for Neuroscience
PY  - 2007
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - The cellular diversity of the cerebral cortex is thought to arise from progenitors located in the ventricular zone and subventricular zone in the telencephalon. Here we describe a novel source of progenitors located outside these two major germinative zones of the mouse cerebral cortex that contributes to neurogenesis and gliogenesis. Proliferating cells first appear in the preplate of the embryonic cerebral cortex and further increase in the marginal zone during mid and late neurogenesis. The embryonic marginal zone progenitors differ in their molecular characteristics as well as the size and identity of their clonal progeny from progenitors isolated from the ventricular zone and subventricular zone. Time-lapse video microscopy and clonal analysis in vitro revealed that the marginal zone progenitor pool contains a large fraction of oligodendrocyte or astrocyte progenitors, as well as neuronal and bipotent progenitors. Thus, marginal zone progenitors are heterogenous in regard to their fate specification, as well as in regard to their region of origin (pallial and subpallial) as revealed by in vivo fate mapping. The local environment in the marginal zone tightly regulates the size of this novel progenitor pool, because both basement membrane defects in laminin{gamma}1–/– mice or alterations in the cellular composition of the marginal zone in Pax6 Small Eye mutant mice lead to an increase in the marginal zone progenitor pool. In conclusion, we have identified a novel source of neuronal and glial progenitors in the marginal zone of the developing cerebral cortex with properties notably distinct from those of ventricular zone and subventricular zone progenitors.
AU  - Costa, M.R.
AU  - Kessaris, N.*
AU  - Richardson, W.D.*
AU  - Götz, M.
AU  - Hedin-Pereira, C.*
C1  - 3191
C2  - 24676
SP  - 11376-11388
TI  - The marginal zone/layer i as a novel niche for neurogenesis and gliogenesis in developing cerebral cortex.
JO  - J. Neurosci.
VL  - 27
IS  - 42
PB  - Society for Neuroscience
PY  - 2007
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Mutations in the parkin gene are a major cause of autosomal recessive Parkinson's disease. Here we show that the E3 ubiquitin ligase parkin activates signaling through the I{kappa}B kinase (IKK)/nuclear factor {kappa}B (NF-{kappa}B) pathway. Our analysis revealed that activation of this signaling cascade is causally linked to the neuroprotective potential of parkin. Inhibition of NF-{kappa}B activation by an I{kappa}B super-repressor or a kinase-inactive IKKß interferes with the neuroprotective activity of parkin. Furthermore, pathogenic parkin mutants with an impaired neuroprotective capacity show a reduced ability to stimulate NF-{kappa}B-dependent transcription. Finally, we present evidence that parkin interacts with and promotes degradation-independent ubiquitylation of IKK{gamma}/NEMO (NF-{kappa}B essential modifier) and TRAF2 [TNF (tumor necrosis factor) receptor-associated factor 2], two critical components of the NF-{kappa}B pathway. Thus, our results support a direct link between the neuroprotective activity of parkin and ubiquitin signaling in the IKK/NF-{kappa}B pathway
AU  - Henn, I.H.*
AU  - Bouman, L.*
AU  - Schlehe, J.S.*
AU  - Schlierf, A.*
AU  - Schramm, J.E.*
AU  - Wegener, E.
AU  - Nakaso, K.*
AU  - Culmsee, C.*
AU  - Berninger, B.*
AU  - Krappmann, D.
AU  - Tatzelt, J.*
AU  - Winklhofer, K.F.*
C1  - 3443
C2  - 24373
SP  - 1868-1878
TI  - Parkin Mediates Neuroprotection through Activation of I{kappa}B Kinase/Nuclear Factor-{kappa}B Signaling.
JO  - J. Neurosci.
VL  - 27
IS  - 8
PB  - Society for Neuroscience
PY  - 2007
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Adult neurogenesis is restricted to two distinct areas of the mammalian brain: the olfactory bulb (OB) and the dentate gyrus (DG). Despite its spatial restriction, adult neurogenesis is of crucial importance for sensory processing and learning and memory. Although it has been shown that tens of thousands of new neurons arrive in the OB and DG every day with about half of them surviving after integration, the total contribution of adult neurogenesis to the pre-existing network remains mostly unknown. This is because of previous approaches labeling only a small proportion of adult-generated neurons. Here, we used genetic fate mapping to follow the majority of adult-generated neurons over long periods. Our data demonstrate two distinct modes of neuron addition to the pre-existing network. In the glomerular layer of the OB, there is a constant net addition of adult-generated neurons reaching a third of the total neuronal population within 9 months. In contrast, adult neurogenesis contributes to only a minor fraction of the entire neuronal network in the granular cell layer of the OB and the DG. Although the fraction of adult generated neurons can be further increased by an enriched environment, it still remains a minority of the neuronal network in the DG. Thus, neuron addition is distinct and tightly regulated in the neuronal networks that incorporate new neurons life long.
AU  - Ninkovic, J.
AU  - Mori, T.
AU  - Götz, M.-L.
C1  - 179
C2  - 24683
SP  - 10906-10911
TI  - Distinct modes of neuron addition in adult mouse neurogenesis.
JO  - J. Neurosci.
VL  - 27
IS  - 40
PB  - Society for Neuroscience
PY  - 2007
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Retinitis pigmentosa (RP) is an inherited blinding disease for which there is no treatment available. It is characterized by a progressive and neurodegenerative loss of photoreceptors but the underlying mechanisms are poorly understood. Excessive activation of the enzyme poly(ADP-ribose) polymerase (PARP) has recently been shown to be involved in several neuropathologies. To investigate the possible role of PARP in retinal photoreceptor degeneration, we used the retinal degeneration 1 (rd1) mouse RP model to study PARP expression, PARP activity, and to test the effects of PARP inhibition on photoreceptor viability. PARP expression was found to be equal between rd1 and wild-type counterpart retinas. In contrast to this, a dramatic increase in both PARP activity per se and PARP product formation was detected by in situ assays in rd1 photoreceptors actively undergoing cell death. Furthermore, PARP activity colabeled with oxidatively damaged DNA and nuclear translocation of AIF (apoptosis-inducing factor), suggesting activation of PARP as a bridge between these events in the degenerating photoreceptors. The PARP-specific inhibitor PJ34 [N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide x HCl[ reduced the number of cells exhibiting death markers in a short-term retinal culture paradigm, a protective effect that was translated into an increased number of surviving photoreceptors when the inhibitor was used in a long-term culture setting. Our results thus demonstrate an involvement of PARP activity in rd1 photoreceptor cell death, which could have a bearing on the understanding of neurodegenerations as such. The findings also suggest that the therapeutical possibilities of PARP inhibition should include retinal diseases like RP.
AU  - Paquet-Durand, F.*
AU  - Silva, J.*
AU  - Talukdar, T.*
AU  - Johnson, L.E.*
AU  - Azadi, S.*
AU  - van Veen, T.*
AU  - Ueffing, M.
AU  - Hauck, S.M.
AU  - Ekström, P.A.*
C1  - 3632
C2  - 24661
SP  - 10311-10319
TI  - Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse.
JO  - J. Neurosci.
VL  - 27
IS  - 38
PB  - Society for Neuroscience
PY  - 2007
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Fibroblast growth factors (FGFs) secreted from the midbrain-rhombomere 1 (r1) boundary instruct cell behavior in the surrounding neuroectoderm. For example, a combination of FGF and sonic hedgehog (SHH) can induce the development of the midbrain dopaminergic neurons, but the mechanisms behind the action and integration of these signals are unclear. We studied how FGF receptors (FGFRs) regulate cellular responses by analyzing midbrain-r1 development in mouse embryos, which carry different combinations of mutant Fgfr1, Fgfr2, and Fgfr3 alleles. Our results show that the FGFRs act redundantly to support cell survival in the dorsal neuroectoderm, promote r1 tissue identity, and regulate the production of ventral neuronal populations, including midbrain dopaminergic neurons. The compound Fgfr mutants have apparently normal WNT/SHH signaling and neurogenic gene expression in the ventral midbrain, but the number of proliferative neural progenitors is reduced as a result of precocious neuronal differentiation. Our results suggest a SoxB1 family member, Sox3, as a potential FGF-induced transcription factor promoting progenitor renewal. We propose a model for regulation of progenitor cell self-renewal and neuronal differentiation by combinatorial intercellular signals in the ventral midbrain.
AU  - Saarimäki-Vire, J.*
AU  - Peltopuro, P.*
AU  - Lahti, L.*
AU  - Naserke, T.
AU  - Blak, A.A.
AU  - Vogt Weisenhorn, D.M.
AU  - Yu, K.*
AU  - Ornitz, D.M.
AU  - Wurst, W.
AU  - Partanen, J.*
C1  - 4900
C2  - 24856
SP  - 8581-8592
TI  - Fibroblast growth factor receptors cooperate to regulate neural progenitor properties in the developing midbrain and hindbrain.
JO  - J. Neurosci.
VL  - 27
IS  - 32
PB  - Society for Neuroscience
PY  - 2007
SN  - 0270-6474
ER  - 

TY  - JOUR
AU  - Köster, R.W.
AU  - Fraser, S.E.*
C1  - 5184
C2  - 23650
SP  - 7293-7304
TI  - FGF signaling mediates regeneration of the differentiating cerebellum through repatterning of the anterior hindbrain and reinitiation of neuronal migration.
JO  - J. Neurosci.
VL  - 26
PY  - 2006
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Most cortical interneurons are generated in the subpallial ganglionic eminences and migrate tangentially to their final destinations in the neocortex. Within the cortex, interneurons follow mainly stereotype routes in the subventricular zone/intermediate zone (SVZ/IZ) and in the marginal zone. It has been suggested that interactions between invading interneurons and locally generated projection neurons are implicated in the temporal and spatial regulation of the invasion process. However, so far experimental evidence for such interactions is lacking. We show here that the chemokine stromal-derived factor 1 (SDF-1; CXCL12) is expressed in the main invasion route for cortical interneurons in the SVZ/IZ. Most SDF-1-positive cells are proliferating and express the homeodomain transcription factors Cux1 and Cux2. Using MASH-1 mutant mice in concert with the interneuron marker DLX, we exclude that interneurons themselves produce the chemokine in an autocrine manner. We conclude that the SDF-1-expressing cell population represents the precursors of projection neurons during their transition and amplification in the SVZ/IZ. Using mice lacking the SDF-1 receptor CXCR4 or Pax6, we demonstrate that SDF-1 expression in the cortical SVZ/IZ is essential for recognition of this pathway by interneurons. These results represent the first evidence for a molecular interaction between precursors of projection neurons and invading interneurons during corticogenesis.
AU  - Tiveron, M.-C.*
AU  - Rossel, M.*
AU  - Moepps, B.*
AU  - Zhang, Y.L.*
AU  - Seidenfaden, R.*
AU  - Favor, J.
AU  - König, N.*
AU  - Cremer, H.*
C1  - 5256
C2  - 24183
SP  - 13273-13278
TI  - Molecular interaction between projection neuron precursors and invading interneurons via stromal-derived factor 1 (CXCL12)/CXCR4 signaling in the cortical subventricular zone/intermediate zone.
JO  - J. Neurosci.
VL  - 26
IS  - 51
PY  - 2006
SN  - 0270-6474
ER  - 

TY  - JOUR
AU  - Roselli, F.*
AU  - Tirard, M.*
AU  - Lu, J.*
AU  - Hutzler, P.
AU  - Lamberti, P.*
AU  - Livrea, P.*
AU  - Morabito, M.*
AU  - Almeida, O.F.X.
C1  - 4046
C2  - 23469
SP  - 11061-11070
TI  - Soluble ß-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses.
JO  - J. Neurosci.
VL  - 25
IS  - 48
PY  - 2005
SN  - 0270-6474
ER  - 

TY  - JOUR
AB  - Midbrain dopaminergic and hindbrain serotonergic neurons play an important role in the modulation of behavior and are involved in a series of neuropsychiatric disorders. Despite the importance of these cells, little is known about the molecular mechanisms governing their development. During embryogenesis, midbrain dopaminergic neurons are specified rostral to the midbrain - hindbrain organizer ( MHO), and hindbrain serotonergic neurons are specified caudal to it. We report that in transgenic mice in which Otx2 and accordingly the MHO are shifted caudally, the midbrain dopaminergic neuronal population expands to the ectopically positioned MHO and is enlarged. Complementary, the extension of the hindbrain serotonergic cell group is decreased. These changes are preserved in adulthood, and the additional, ectopic dopaminergic neurons project to the striatum, which is a proper dopaminergic target area. In addition, in mutants in which Otx2 and the MHO are shifted rostrally, dopaminergic and serotonergic neurons are relocated at the newly positioned MHO. However, in these mice, the size ratio between these two cell populations is changed in favor of the serotonergic cell population. To investigate whether the position of the MHO during embryogenesis is also of functional relevance for adult behavior, we tested mice with a caudally shifted MHO and report that these mutants show a higher locomotor activity. Together, we provide evidence that the position of the MHO determines the location and size of midbrain dopaminergic and hindbrain serotonergic cell populations in vivo. In addition, our data suggest that the position of the MHO during embryogenesis can modulate adult locomotor activity.
AU  - Brodski, C.*
AU  - Vogt Weisenhorn, D.M.
AU  - Signore, M.*
AU  - Sillaber, I.*
AU  - Oesterheld, M.*
AU  - Broccoli, V.*
AU  - Acampora, D.*
AU  - Simeone, A.*
AU  - Wurst, W.
C1  - 4385
C2  - 21733
SP  - 4199-4207
TI  - Location and size of dopaminergic and serotonergic cell populations are controlled by the position of the midbrain-hindbrain organizer.
JO  - J. Neurosci.
VL  - 23
IS  - 10
PY  - 2003
SN  - 0270-6474
ER  - 

TY  - JOUR
AU  - Simon, H.H.*
AU  - Saueressig, H.*
AU  - Wurst, W.
AU  - Goulding, M.D.*
AU  - O'Leary, D.D.M.*
C1  - 786
C2  - 22815
SP  - 3126-3134
TI  - Fate of midbrain dopaminergic neurons controlled by the engrailed genes.
JO  - J. Neurosci.
VL  - 21
PY  - 2001
SN  - 0270-6474
ER  -