A key function of neurotrophins is to regulate the formation and refinement of synaptic connections in the central nervous system (CNS). Since the initial discovery of nerve growth factor (NGF), a member of the neurotrophin family, extensive efforts have been made to identify and elucidate the cellular actions of neurotrophins. Like other secreted proteins, neurotrophins arise from precursors, pro-neurotrophins (30-35 kDa), which are proteolytically cleaved to produce mature proteins (12-13 kDa). In the mammalian brain, four members of the neurotrophin family have been identified: NGF, brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). These closely related molecules act by binding to two distinct classes of transmembrane receptors: the

'Section on Neural Development & Plasticity, NICHD; Genes, Cognition and Psychosis Program (GCAP), NIMH, National Institutes of Health, Bethesda, MD 20892-3714; [email protected]

p75 pan-neurotrophin receptor (p75NTR) and the Trk family of receptor tyrosine kinases. All neurotrophins bind p75NTR with similar affinity. In contrast, Trk receptor kinases interact selectively with a different neurotrophin: BDNF and NT-4 bind to TrkB, NGF to TrkA and NT-3 to TrkC. This diversity in receptor and ligand interactions, as well as the distinct patterns of expression in several critical regions of the brain, underscores the importance of neurotrophins in regulating many facets of neural development.

Normal function of the brain requires the formation of complex neuronal networks built on numerous synaptic connections that are appropriately formed and maintained. This is the result of a multistep process occurring throughout development that involves neurogenesis, survival, differentiation, and dendritic and axonal growth. The final step culminates in the formation of synapses, also known as synaptogenesis. Not limited to development, synaptogenesis also occurs during normal cognitive functions in the adult brain such as learning and memory, as well as during regeneration after brain injury. It is now recognized that synaptogenesis itself is a multistep process that includes initial synaptic contact, maturation, and stabilization. In addition, excessive and inappropriate synapses also need to be eliminated, and this process requires co-incident activity between pre- and postsynaptic partners.

Recent studies have shown that neurotrophins influence various aspects of synaptogenesis. In this chapter we highlight the diverse signal transduction cascades utilized by neurotrophins to regulate synapse formation, and discuss the functional roles of neurotrophins at different stages of synaptogenesis by focusing on several regions of the brain. We start out with an overview of the signaling cascades that are activated by neurotrophins. We next discuss the role of neurotrophins in synaptogenesis in a simple system: the neuromuscular junction (NMJ). Subsequently, we examine the formation of synapses in the developing hippocampus and cerebellum. We then discuss how neurotrophins regulate the formation of ocular dominance during visual cortex (VC) development, an example of how neurotrophins refine synaptic connections. Finally we provide evidence for neurotrophic regulation of synaptic connections in the adult or mature organism as observed in the case of the barrel cortex.

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