During development of the central nervous system (CNS), precise synaptic connections between pre- and postsynaptic neurons are formed that ultimately give rise to higher order cognitive skills such as learning and memory. Previously, my group identified a novel type II transmembrane protein, synapse differentiation induced gene 1 (SynDIG1), that regulates synaptic AMPA receptor content in dissociated rat hippocampal neurons. The magnitude of this effect matches that of the prototypical scaffold postsynaptic density protein of 95 kDa (PSD-95) identifying SynDIG1 as a previously unknown central regulator of excitatory synaptic strength. SynDIG1-mediated regulation of synaptic AMPA receptor targeting shares characteristics related to two distinct classes of transmembrane synaptic proteins: (1) ion channel auxiliary factors such as transmembrane AMPA receptor regulatory proteins (TARPs) important for AMPA receptor surface expression and channel gating properties; and (2) trans-synaptic organizing molecules such as leucine rich repeat transmembrane protein 2 (LRRTM2) that influence synapse maturation by recruitment of AMPA receptors to nascent synapses. An interesting aspect of SynDIG1 is that its distribution at excitatory synapses is regulated by activity, suggesting that SynDIG1 might also play a role in synaptic plasticity.
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