UC Davis

Trafficking, localization, and biophysical properties of AMPA-type glutamate receptors (AMPARs) at synapses are predominant mechanisms for regulating synaptic strength underlying learning and memory. AMPARs are highly regulated by a number of auxiliary proteins such as TARPs, cornichons, and CKAMPs, as well as the members of the SynDIG/Prrt family, which will be the focus of this study. Previous studies of the transmembrane protein Synapse Differentiation Induced Gene 1 (SD1; SD1) as an AMPAR interacting protein that regulates excitatory synaptic strength and AMPAR number both in vitro and in vivo. The SynDIG family is defined by a family of four genes, SD1-4, which are expressed in distinct locations within the brain. SynDIG4 (SD4/Prrt1) is primarily expressed within the hippocampus, the main site of memory formation in both mice and humans. SD4 was identified in several independent proteomic screens in complex with AMPARs, suggesting it may also function as an AMPAR auxiliary factor. We previously observed that long-term potentiation (LTP) is abolished by single tetanus stimulation of hippocampal slices from SD4 knockout (KO) mice. In this study we demonstrate that only specific protein domains are necessary for clustering of AMPARs and SD4. Furthermore, we observed that some SD4 co-localizes with extra-synaptic GluA1-containing AMPARs in primary neurons, while loss of SD4 results in reduced extra-synaptic AMPARs, implying a role of SD4 outside the synapse. We hypothesize that SD4 regulates AMPARs through maintenance of an extra-synaptic pool of GluA1-containing AMPARs required for trafficking and LTP.