SynDIG1 regulation of synaptic AMPA receptor targeting.

Excitatory synapses are composed of several specialized domains including the presynaptic bouton containing several hundred synaptic vesicles (svs), the presynaptic active zone where svs dock and fuse with the plasma membrane, and the juxtaposed postsynaptic density (psd) composed of an electron dense meshwork of proteins including nmda and ampa receptors, ion channels, and various signaling components. cell adhesion molecules (cams) extend across the synaptic cleft to stabilize this macromolecular complex. during development of the central nervous system (cns), certain cams also serve as inductive signals that trigger the establishment of pre- and postsynaptic specializations.1-4 Early events in synapse development include clustering of SVs to the active zone and NMDA receptors to the PSD, whereas later events include targeting of AMPA receptors and synaptic activity that might direct whether synapses will be stabilized, eliminated or strengthened. Regulating the number of AMPA receptors located at the PSD is a key mechanism underlying synaptic strength and plasticity implicated in learning and memory.5-10 Thus, a current avenue of investigation is the identification of interacting proteins that influence targeting of synaptic AMPA receptors. The discovery that the transmembrane protein stargazin controls synaptic AMPA-R targeting represented a major paradigm shift in the field.11 My colleagues and I recently reported the discovery of a novel type II transmembrane protein SynDIG1 (Synapse Differentiation Induced Gene I) that functions as a critical regulator of excitatory synapse development in dissociated rat hippocampal neurons.12 Specifically, knock-down of SynDIG1 in cultured neurons reduces AMPA receptor content at developing synapses by approximately 50% as determined by immunocytochemistry and electrophysiology.12 The magnitude of this effect matches that of TARPs and PSD-95 identifying SynDIG1 as a previously unknown central regulator of postsynaptic AMPA receptor targeting. In this addendum I further discuss the implications of these data.