Neuron-Specific Gene 2 (NSG2) Encodes an AMPA Receptor Interacting Protein That Modulates Excitatory Neurotransmission

Neurons have evolved a number of unique protein-coding genes that regulate trafficking of protein complexes within small organelles throughout dendrites and axons. Neuron-specific gene 2 (NSG2) encodes for one of the most abundant proteins in the nervous system during perinatal development. NSG2 belongs to a family of small neuronal endosomal proteins but its function has remained uncharacterized to date. Here, we show that NSG2 is found in discrete punctae restricted to the somatodendritic arbors of developing mouse and human neurons, and a significant proportion of NSG2 punctae colocalize with postsynaptic HOMER1 and surface-expressed AMPA-type glutamate receptors (AMPARs) at excitatory synapses. Immunoprecipitation revealed that NSG2 physically interacts with both the GluA1 and GluA2 AMPAR subunits in mouse brain. Knock-out of NSG2 in mouse hippocampal neurons selectively impaired the frequency of miniature EPSCs (mEPSCs) and caused alterations in PSD95 expression at postsynaptic densities (PSDs). In contrast, NSG2 overexpression caused a significant increase in the amplitude of mEPSCs as well as GluA2 surface expression. Thus, NSG2 functions as an AMPAR-binding protein that is required for normal synapse formation and/or maintenance, and has unique functions compared with other NSG family members.