[S46]: Otx2 homeoprotein specifies critical period plasticity in mouse visual cortex

Abstract

SHP-2 enhanced neurogenesis and suppressed gliogenesis. Blockade of MAP kinase activity inhibited the SHP-2-mediated increase in neurogenesis, indicating that this is the likely pathway used by NS SHP-2. Together, these results indicate that SHP-2 plays a key role in integrating extrinsic signals, and functions to promote neurogenesis at the same time that it inhibits gliogenesis. We are currently investigating whether the neuronal versus glial ratio is altered in a mouse model of Noonan syndrome, with the ultimate goal of determining whether this accounts for the cognitive impairments in NS patients. Cellular mechanisms regulating neural plasticity [S45]Role of proteolytic conversion of proBDNF to mBDNF in synaptic development and plasticity B. LuGene, Cognition and Psychosis (GCAP) Program, NIMH, NIH, USA BDNF has recently emerged as a key regulator for synaptic development and plasticity. In a recent study, we examined the role of BDNF in late-phase LTP (L-LTP). We demonstrate that the extracellular protease tPA converts the precursor proBDNF to the mature BDNF (mBDNF) in the hippocampus, and such conversion is critical for L-LTP. Furthermore, application of mBDNF allows L-LTP to occur when protein synthesis is blocked and converts early-phase LTP to L-LTP, suggesting that mBDNF is the key protein synthesis product responsible for L-LTP expression. Our study has identified tPA/plasmin as an endogenous enzyme system that converts proBDNF to mBDNF in the hippocampus, and provided a mechanistic link between tPA and BDNF in L-LTP.ProBDNF and mBDNF are thought to bind to two distinct receptors: the pan neurotrophin receptor p75 (p75 NTR ) and the TrkB tyrosine kinase, respectively. Previous, studies indicate that mBDNF facilitates LTP through TrkB. We show that the proBDNF, by activating its preferred receptor p75 NTR , selectively enhances the NMDA-dependent form of LTD at the hippocampal synapses. Together with the finding that mBDNF promotes LTP, our results support a Yin-Yang model in which proBDNF promotes LTD whereas mBDNF facilitates LTP. Thus, extracellular cleavage of proBDNF becomes a key step that controls the direction of BDNF regulation.ProBDNF ! mBDNF conversion may also play a role in synapse development. Using a cell culture system in which a single myocyte is innervated by two spinal neurons, proBDNF induces retraction of the less active terminal by activating p75 NTR , whereas mature BDNF (mBDNF) facilitates the stabilization of the active one through TrkB. Muscle activity drives the secretion of proBDNF, which is converted to mBDNF by proteases selectively expressed by the active, presynaptic terminal. These results demonstrate that the activity-dependent conversion of proBDNF to mBDNF is critical for synaptic competition and elimination during development.Brain functions are shaped by sensory experience during early postnatal life. We have found that the critical period for binocular vision is triggered by specific GABAergic connections in the neocortex. Maturation of these interneurons (and hen...