SynDIG4/Prrt1 Is Required for Excitatory Synapse Development and Plasticity Underlying Cognitive Function

Summary Altering AMPA receptor(AMPAR) content at synapsesis a key mechanism underlying the regulation of synaptic strength during learning and memory. Previous work demonstrated that SynDIG1 ( synapsedifferentiation-induced gene 1) encodes a transmembrane AMPAR-associated protein that regulates excitatory synapsestrength and number. Here we show that the related protein SynDIG4 (also known as Prrt1) modifies AMPAR gating properties in a subunit-dependent manner. Young SynDIG4 knockout (KO) mice have weaker excitatory synapses, as evaluated by immunocytochemistryand electrophysiology. Adult SynDIG4 KO mice show complete loss of tetanus-induced long-term potentiation(LTP), while mEPSC amplitude is reduced by only 25%. Furthermore, SynDIG4 KO mice exhibit deficits in two independent cognitive assays. Given that SynDIG4 colocalizes with the AMPAR subunit GluA1 at non-synaptic sites, we propose that SynDIG4 maintains a pool of extrasynaptic AMPARs necessary for synapsedevelopment and function underlying higher-order cognitive plasticity.