TY - JOUR AB - Degeneration or damage of neuronal circuits in the central nervous system can lead to an irreversible loss of neurons and function in the affected brain region. Neuronal transplantation is a promising therapeutic approach consisting of introducing healthy cells into the damaged or diseased regions to restore lost circuits. To achieve successful neuronal transplantation, proper integration of the graft in the host circuitry is necessary. This includes the restoration of connectivity as well as the recapitulation of the physiological characteristics of the lost endogenous neurons. An often-overlooked aspect to assess the integration of transplanted neurons is the acquisition of cell-extrinsic features, such as myelination. This review explores the interaction between transplanted cells and endogenous oligodendroglia, the evidence of myelination in different neuronal transplantation models, and the checkpoints that can influence graft myelination in the injured or diseased brain. Additionally, it discusses how appropriate myelin ensheathment could help overcome some challenges faced in the field of neuronal replacement. AU - Martinez-Reza, M.F. AU - Götz, M. C1 - 75849 C2 - 58149 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Wrap it up: Myelination of transplanted neurons for repair. JO - Front. Cell. Neurosci. VL - 19 PB - Frontiers Media Sa PY - 2025 ER - TY - JOUR AB - The repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is an epigenetic master regulator that plays a crucial role during nervous system development and maturation. REST function was originally described during development, where it determines neuronal phenotype. However, recent studies showed that REST participates in several processes in the adult brain, including neuronal plasticity and epileptogenesis. In this regard, the relationships between REST and epilepsy are still controversial and need further investigation. As forebrain excitatory neurons are the common final pathway of seizure susceptibility, we investigated the role of REST in epilepsy by inducing REST conditional knockout (REST-cKO) specifically in excitatory neurons of the hippocampus. To target the excitatory neuronal population, we cloned the calcium/calmodulin-dependent protein kinase IIα minimal promoter upstream of Cre recombinase. After assessing the specificity of the promoter's expression, the transgenes were packaged in an engineered adeno-associated virus able to cross the blood-brain and blood-cerebrospinal fluid barriers and delivered in the lateral ventricles of 2-month-old RESTflox/flox mice to characterize, after 1 month, the cognitive phenotype and the seizure propensity. We show that REST-cKO mice display lower levels of anxiety in the light-dark test with respect to control mice but have unaltered motor, social, and cognitive profiles. The evaluation of the susceptibility to epileptic seizures showed that REST-cKO mice are more resistant to pentylenetetrazole-induced kindling but not to seizures induced by a single administration of the convulsant and show higher survival rates. Overall, these data suggest that the absence of REST in forebrain excitatory neurons decreases seizure susceptibility, pointing to a pro-epileptogenic role of the transcriptional repressor under conditions of pathological excitation/inhibition imbalance. AU - Natali, G.* AU - Michetti, C.* AU - Krawczun-Rygmaczewska, A.* AU - Floss, T. AU - Cesca, F.* AU - Benfenati, F.* C1 - 68889 C2 - 53745 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Conditional knockout of REST/NRSF in excitatory neurons reduces seizure susceptibility to chemical kindling. JO - Front. Cell. Neurosci. VL - 17 PB - Frontiers Media Sa PY - 2023 ER - TY - JOUR AB - Pericytes (PCs) are essential components of the blood brain barrier. Brain PCs are critical for dynamically regulating blood flow, for maintaining vascular integrity and their dysregulation is associated with a myriad of disorders such as Alzheimer's disease. To understand their physiological and molecular functions, studies have increasingly focused on primary brain PC isolation and culture. Multiple methods for PC culture have been developed over the years, however, it is still unclear how primary PCs compare to their in vivo counterparts. To address this question, we compared cultured brain PCs at passage 5 and 20 to adult and embryonic brain PCs directly isolated from mouse brains via single cell RNA-seq. Cultured PCs were highly homogeneous, and were most similar to embryonic PCs, while displaying a significantly different transcriptional profile to adult brain PCs. Cultured PCs downregulated canonical PC markers and extracellular matrix (ECM) genes. Importantly, expression of PC markers and ECM genes could be improved by co-culture with brain endothelial cells, showing the importance of the endothelium in maintaining PC identity and function. Taken together, these results highlight key transcriptional differences between cultured and in vivo PCs which should be considered when performing in vitro experiments with brain PCs. AU - Oliveira, F. AU - Bondareva, O. AU - Rodriguez Aguilera, J.R. AU - Sheikh, B. C1 - 67920 C2 - 54398 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Cultured brain pericytes adopt an immature phenotype and require endothelial cells for expression of canonical markers and ECM genes. JO - Front. Cell. Neurosci. VL - 17 PB - Frontiers Media Sa PY - 2023 ER - TY - JOUR AB - Central nervous system (CNS) injury results in chronic scar formation that interferes with function and inhibits repair. Extracellular matrix (ECM) is prominent in the scar and potently regulates cell behavior. However, comprehensive information about the ECM proteome is largely lacking, and region- as well as injury-specific differences are often not taken into account. These aspects are the focus of our perspective on injury and scar formation. To highlight the importance of such comprehensive proteome analysis we include data obtained with novel analysis tools of the ECM composition in the scar and show the contribution of monocytes to the ECM composition after traumatic brain injury (TBI). Monocyte invasion was reduced using the CCR2-/- mouse line and step-wise de-cellularization and proteomics allowed determining monocyte-dependent ECM composition and architecture of the glial scar. We find significant reduction in the ECM proteins Tgm1, Itih (1,2, and 3), and Ftl in the absence of monocyte invasion. We also describe the scar ECM comprising zones with distinctive composition and show a subacute signature upon comparison to proteome obtained at earlier times after TBI. These results are discussed in light of injury-, region- and time-specific regulation of scar formation highlighting the urgent need to differentiate injury conditions and CNS-regions using comprehensive ECM analysis. AU - Kjell, J. AU - Götz, M. C1 - 58548 C2 - 48249 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Filling the gaps - A call for comprehensive analysis of extracellular matrix of the glial scar in region- and injury-specific contexts. JO - Front. Cell. Neurosci. VL - 14 PB - Frontiers Media Sa PY - 2020 ER - TY - JOUR AB - Disorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor--in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic and cellular analysis of both variants confirmed them to be loss-of-function with enhanced sensitivity to transcript degradation via nonsense mediated decay (NMD) or increased protein turnover via the proteasome. Knockdown ofwithin the developing mouse cortex demonstrated its role in neuronal positioning. Cilia positioning and number within migrating neurons was also impaired with comparable defects detected following a reduction in levels of an upstream modulator of Mob2 function, Dchs1, a previously identified locus associated with PH. Moreover, reduced Mob2 expression increased phosphorylation of Filamin A, an actin cross-linking protein frequently mutated in cases of this disorder. These results reveal a key role for Mob2 in correct neuronal positioning within the developing cortex and outline a new candidate locus for PH development. AU - O'Neill, A.C. AU - Kyrousi, C.* AU - Einsiedler, M. AU - Burtscher, I. AU - Drukker, M. AU - Markie, D.M.* AU - Kirk, E.P.* AU - Götz, M. AU - Robertson, S.P.* AU - Cappello, S.* C1 - 53326 C2 - 44661 CY - Lausanne TI - Mob2 insufficiency disrupts neuronal migration in the developing cortex. JO - Front. Cell. Neurosci. VL - 12 PB - Frontiers Media Sa PY - 2018 ER - TY - JOUR AB - During brain development, radial glial cells possess an apico-basal polarity and are coupled by adherens junctions (AJs) to an F-actin belt. To elucidate the role of the actin, we conditionally deleted the key component α-E-catenin in the developing cerebral cortex. Deletion at early stages resulted in severe disruption of tissue polarity due to uncoupling of AJs with the intracellular actin fibers leading to the formation of subcortical band heterotopia. Interestingly, this phenotype closely resembled the phenotype obtained by conditional RhoA deletion, both in regard to the macroscopic subcortical band heterotopia and the subcellular increase in G-actin/F-actin ratio. These data therefore together corroborate the role of the actin cytoskeleton and its anchoring to the AJs for neuronal migration disorders. AU - Schmid, M.-T. AU - Weinandy, F. AU - Wilsch-Bräuninger, M.* AU - Huttner, W.B.* AU - Cappello, S. AU - Götz, M. C1 - 32000 C2 - 34928 CY - Lausanne TI - The role of α-E-catenin in cerebral cortex development: Radial glia specific effect on neuronal migration. JO - Front. Cell. Neurosci. VL - 8 PB - Frontiers Research Foundation PY - 2014 ER - TY - JOUR AB - Neural stem cells (NSCs) from the subventricular zone (SVZ) have been indicated as a source of new oligodendrocytes to use in regenerative medicine for myelin pathologies. Indeed, NSCs are multipotent cells that can self-renew and differentiate into all neural cell types of the central nervous system. In normal conditions, SVZ cells are poorly oligodendrogenic, nevertheless their oligodendrogenic potential is boosted following demyelination. Importantly, progressive restriction into the oligodendrocyte fate is specified by extrinsic and intrinsic factors, endocannabinoids being one of these factors. Although a role for endocannabinoids in oligodendrogenesis has already been foreseen, selective agonists and antagonists of cannabinoids receptors produce severe adverse side effects. Herein, we show that hemopressin (Hp), a modulator of CB1 receptors, increased oligodendroglial differentiation in SVZ neural stem/progenitor cell cultures derived from neonatal mice. The original results presented in this work suggest that Hp and derivates may be of potential interest for the development of future strategies to treat demyelinating diseases. AU - Xapelli, S.* AU - Agasse, F.* AU - Grade, S. AU - Bernardino, L.* AU - Ribeiro, F.F.* AU - Schitine, C.S.* AU - Heimann, A.S.* AU - Ferro, E.S.* AU - Sebasti, A.M.* AU - de Melo Reis, R.A.* AU - Malva, J.O.* A2 - Gonzalez-Perez, O.* C1 - 30674 C2 - 33856 CY - Lausanne TI - Modulation of subventricular zone oligodendrogenesis: A role for hemopressin? JO - Front. Cell. Neurosci. VL - 8 PB - Frontiers PY - 2014 ER - TY - JOUR AB - Corticotropin-releasing hormone (CRH) plays an important role in a substantial number of patients with stress-related mental disorders, such as anxiety disorders and depression. CRH has been shown to increase neuronal excitability in the hippocampus, but the underlying mechanisms are poorly understood. The effects of CRH on neuronal excitability were investigated in acute hippocampal brain slices. Population spikes (PS) and field excitatory postsynaptic potentials (fEPSP) were evoked by stimulating Schaffer-collaterals and recorded simultaneously from the somatic and dendritic region of CA1 pyramidal neurons. CRH was found to increase PS amplitudes (mean ± Standard error of the mean; 231.8 ± 31.2% of control; n = 10) while neither affecting fEPSPs (104.3 ± 4.2%; n = 10) nor long-term potentiation (LTP). However, when Schaffer-collaterals were excited via action potentials (APs) generated by stimulation of CA3 pyramidal neurons, CRH increased fEPSP amplitudes (119.8 ± 3.6%; n = 8) and the magnitude of LTP in the CA1 region. Experiments in slices from transgenic mice revealed that the effect on PS amplitude is mediated exclusively by CRH receptor 1 (CRHR1) expressed on glutamatergic neurons. The effects of CRH on PS were dependent on phosphatase-2B, L- and T-type calcium channels and voltage-gated potassium channels but independent on intracellular Ca(2+)-elevation. In patch-clamp experiments, CRH increased the frequency and decay times of APs and decreased currents through A-type and delayed-rectifier potassium channels. These results suggest that CRH does not affect synaptic transmission per se, but modulates voltage-gated ion currents important for the generation of APs and hence elevates by this route overall neuronal activity. AU - Kratzer, S.* AU - Mattusch, C.* AU - Metzger, M.W.* AU - Dedic, N. AU - Noll-Hussong, M.* AU - Kafitz, K.W.* AU - Eder, M.* AU - Deussing, J.M. AU - Holsboer, F.* AU - Kochs, E.* AU - Rammes, G.* C1 - 26172 C2 - 32105 TI - Activation of CRH receptor type 1 expressed on glutamatergic neurons increases excitability of CA1 pyramidal neurons by the modulation of voltage-gated ion channels. JO - Front. Cell. Neurosci. VL - 7 PB - Frontiers Research Foundation PY - 2013 ER -