Cellular and Molecular Mechanisms of Synaptic Specificity

Abstract

All nervous system functions rely upon the specificity of synapse formation and maturation, and the experience-dependent remodeling of established synapses. Activity- and neurotrophic factor (NTF)-dependent signaling events guide the appropriate expression and localization of various components of pre- and postsynaptic machinery to ensure synaptic network function is matched to the behavioral requirements of an animal. These processes govern the function of the individual synapses formed by any given neuron, although the underlying cellular and molecular mechanisms have not been fully defined. To determine postsynaptic mechanisms of synaptic specificity, I investigated the role of menin, the product of the MEN1 tumor suppressor gene, in promoting cholinergic postsynaptic function in response to NTFs. Here, I present the first direct evidence for the molecular actions of menin in neurons, which coordinates the selective transcriptional upregulation and postsynaptic clustering of neuronal nicotinic acetylcholine receptors (nAChR). This occurs through distinct actions of proteolytic fragments generated by activity-dependent calpain cleavage. These data identify a novel synaptogenic mechanism for the coordination of nuclear transcription and postsynaptic localization of neurotransmitter receptors by a single gene product, and identify menin as a candidate molecular scaffold for neuronal nAChR clustering. To determine presynaptic mechanisms of synaptic specificity, I investigated how a co-transmitting neuron selectively employs classical or peptide neurotransmitters at synapses with distinct postsynaptic targets. Here, I present the first evidence that the function of individual presynaptic terminals is differentiated in a target cell-specific manner by an interplay between NTF and retrograde arachidonic acid signaling. I found that presynaptic transmitter specificity was defined by regulated synaptophysin expression, which selectively inhibited neuropeptide release machinery. These observations identify a novel role for synaptophysin in the regulation of peptidergic synaptic transmission, and a new component of NTF-dependent synaptic plasticity through which the co-transmitter characteristics of individual presynaptic terminals are regulated. Together, these studies delineate novel mechanisms underlying activity- and NTF-dependent synaptic specificity, underscoring the importance of appropriate expression and localization of synaptic machinery in controlling neuronal network function via the specialization of individual synapses. These findings provide fundamental mechanistic insights into the neurodevelopmental, neuropsychiatric, and neurodegenerative disorders in which these processes are disrupted.