TY - JOUR AB - The bulk of brain energy expenditure is allocated for maintenance of perpetual intrinsic activity of neurons and neural circuits. Long-term electrophysiological and neuroimaging studies in anesthetized and behaving animals show, however, that the great majority of nerve cells in the intact brain do not fire action potentials, i.e., are permanently silent. Herein, I review emerging data suggesting massive redundancy of nerve cells in mammalian nervous system, maintained in inhibited state at high energetic costs. Acquired in the course of evolution, these collections of dormant neurons and circuits evade routine functional undertakings, and hence, keep out of the reach of natural selection. Under penetrating stress and disease, however, they occasionally switch in active state and drive a variety of neuro-psychiatric symptoms and behavioral abnormalities. The increasing evidence for widespread occurrence of silent neurons warrants careful revision of functional models of the brain and entails unforeseen reserves for rehabilitation and plasticity. AU - Ovsepian, S.V. C1 - 55324 C2 - 46254 CY - Tiergartenstrasse 17, D-69121 Heidelberg, Germany SP - 973–983 TI - The dark matter of the brain. JO - Brain Struct. Funct. VL - 224 IS - 3 PB - Springer Heidelberg PY - 2019 SN - 1863-2653 ER - TY - JOUR AB - It has long been held that the rise of neurons as a specialized cell type also marked the onset of the grand evolutionary journey for chemical synapses. Research over recent decades has shown, however, that the most dynamic chapters of synaptic history have been ‘written’ out of the context of neurobiology and neuronal evolution, dating back to the early metazoa and unicellular living forms. Here, I consider and discuss emerging evidence suggesting the exaptive origin of chemical synapses, via tinkering and neo-functionalization of already existent junctional morphologies and constituents of primeval paracrine signalling. Through combination and collateral use of long-established structures and functions, a remarkable enrichment of regulatory and control mechanisms of complex living organisms was achieved, without large-scale reorganization of the genome, with tremendous impact on the evolution and life on our planet. AU - Ovsepian, S.V. C1 - 51410 C2 - 43224 CY - Heidelberg SP - 3369–3374 TI - The birth of the synapse. JO - Brain Struct. Funct. VL - 222 IS - 8 PB - Springer Heidelberg PY - 2017 SN - 1863-2653 ER - TY - JOUR AB - The establishment of the brain structural complexity requires a precisely orchestrated interplay between extrinsic and intrinsic signals modulating cellular mechanisms to guide neuronal differentiation. However, little is known about the nature of these signals in the diencephalon, a complex brain region that processes and relays sensory and motor information to and from the cerebral cortex and subcortical structures. Morphogenetic signals from brain organizers regulate histogenetic processes such as cellular proliferation, migration, and differentiation. Sonic hedgehog (Shh) in the key signal of the ZLI, identified as the diencephalic organizer. Fgf15, the mouse gene orthologous of human, chick, and zebrafish Fgf19, is induced by Shh signal and expressed in the diencephalic alar plate progenitors during histogenetic developmental stages. This work investigates the role of Fgf15 signal in diencephalic development. In the absence of Fgf15, the complementary expression pattern of proneural genes: Ascl1 and Nng2, is disrupted and the GABAergic thalamic cells do not differentiate; in addition dorsal thalamic progenitors failed to exit from the mitotic cycle and to differentiate into neurons. Therefore, our findings indicate that Fgf15 is the Shh downstream signal to control thalamic regionalization, neurogenesis, and neuronal differentiation by regulating the expression and mutual segregation of neurogenic and proneural regulatory genes. AU - Martinez-Ferre, A.* AU - Lloret-Quesada, C.* AU - Prakash, N. AU - Wurst, W. AU - Rubenstein, J.L.* AU - Martinez, S.* C1 - 46765 C2 - 37808 CY - Heidelberg SP - 3095-3109 TI - Fgf15 regulates thalamic development by controlling the expression of proneural genes. JO - Brain Struct. Funct. VL - 221 IS - 6 PB - Springer Heidelberg PY - 2015 SN - 1863-2653 ER - TY - JOUR AB - The prominent tropism of tetanus toxin (TeTx) towards peripheral nerves with retrograde transport and transfer to central neurons render it an invaluable probe for exploring fundamental neuronal processes such as endocytosis, retrograde trafficking and trans-synaptic transport to central neurons. While the specificity of TeTx to nerve cells has been attributed to its binding domains (HC and HCC), molecular determinants of the long-range trafficking that ensure its central delivery and induction of spastic paralysis remain elusive. Here, we report that a protease-inactive TeTx mutant (TeTIM) fused to core streptavidin (CS) proved superior to CS-HC and CS-HCC fragments in antagonizing the internalization of the active toxin in cultured spinal cord neurons. Also, in comparison to CS-HC and CS-HCC, CS-TeTIM undergoes faster clearance from motor nerve terminals after peripheral injection, and is detected in a greater number of neurons in the spinal cord and brain stem ipsi-lateral to the administration site. Consistent with trans-synaptic transfer from motor neurons to inter-neurons, CS-TeTIM infiltrated non-cholinergic cells in the spinal cord; in contrast, the retrograde spread of CS-HC was largely restricted to neurons stained for choline acetyltransferase. Peripheral injection of CS-TeTIM conjugated to a lentivirus encoding mutated SNAP-25, resistant to cleavage by botulinum neurotoxin A, E and C1, rendered spontaneous excitatory postsynaptic currents in motor neurons resilient to challenge by type A toxin in vitro, whereas the same virus conjugated to CS-HC proved ineffective. These findings indicate that full-length inactive TeTx greatly exceeds HC and HCC in targeting and invading motor nerve terminals at the periphery and exploits more efficiently the retrograde transport and trans-synaptic transfer mechanisms of motor neurons to arrive at central neurons. Such qualities render TeTIM a more suitable research probe and neuron-targeting vehicle for retro-axonal delivery of viral vectors to the CNS. AU - Ovsepian, S.V.* AU - Bodeker, M.O.* AU - O'Leary, V.B. AU - Lawrence, G.W.* AU - Dolly, J.O.* C1 - 43437 C2 - 36625 CY - Heidelberg SP - 1825-1838 TI - Internalization and retrograde axonal trafficking of tetanus toxin in motor neurons and trans-synaptic propagation at central synapses exceed those of its C-terminal-binding fragments. JO - Brain Struct. Funct. VL - 220 IS - 3 PB - Springer Heidelberg PY - 2015 SN - 1863-2653 ER - TY - JOUR AU - Ovsepian, S.V.* AU - Bodeker, M.D.* AU - O'Leary, V.B. AU - Lawrence, G.W.* AU - Dolly, J.O.* C1 - 46686 C2 - 37729 TI - Erratum to: Internalization and retrograde axonal trafficking of tetanus toxin in motor neurons and trans-synaptic propagation at central synapses exceed those of its C-terminal-binding fragments. JO - Brain Struct. Funct. VL - 220 IS - 3 PY - 2015 SN - 1863-2653 ER - TY - JOUR AB - A fascinating yet perhaps overlooked trait of the p75 neurotrophin receptor (p75(NTR)) is its ability to bind ligands with no obvious neurotrophic function. Using cultured basal forebrain (BF) neurons, this study demonstrates selective internalization of amyloid beta (A beta) 1-42 in conjunction with p75(NTR) (labelled with IgG192-Cy3) by cholinergic cells. Active under resting conditions, this process was enhanced by high K+ stimulation and was insensitive to inhibitors of regulated synaptic activity-tetrodotoxin or botulinum neurotoxins (BoNT type/A and/B). Blockade of sarco-endoplasmic reticulum (SERCA) Ca2+ ATPase with thapsigargin and CPA or chelation of Ca2+ with EGTA-AM strongly suppressed the endocytosis of p75(NTR), implicating the role of ER released Ca2+. The uptake of IgG192-Cy3 was also reduced by T-type Ca2+ channel blocker mibefradil but not Cd2+, an indiscriminate blocker of high voltage-activated Ca2+ currents. A strong co-localization of IgG192-Cy3 with late endosome (Rab7) or lysosome (Lamp1) qualifier proteins suggest these compartments as the primary destination for internalized IgG192 and A beta. Selective uptake and labeling of BF cholinergic cells with IgG192-Cy3 injected into the prefrontal cortex was verified also in vivo. The significance of these findings in relation to A beta clearance in the cerebral cortex and pathophysiology of Alzheimer's disease is discussed. AU - Ovsepian, S.V.* AU - Antyborzec, I.* AU - O'Leary, V.B. AU - Zaborszky, L.* AU - Herms, J.* AU - Dolly, J.O.* C1 - 32446 C2 - 35051 CY - Heidelberg SP - 1527-1541 TI - Neurotrophin receptor p75 mediates the uptake of the amyloid beta (A β) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons. JO - Brain Struct. Funct. VL - 219 IS - 5 PB - Springer Heidelberg PY - 2014 SN - 1863-2653 ER -