%0 Journal Article %A Praveen Chander %A Matthew J. Kennedy %A Bettina Winckler %A Jason P. Weick %T Neuron-Specific Gene 2 (NSG2) encodes an AMPA receptor interacting protein that modulates excitatory neurotransmission %D 2019 %R 10.1523/ENEURO.0292-18.2018 %J eneuro %P ENEURO.0292-18.2018 %X Neurons have evolved a number of unique protein-coding genes that regulate trafficking of protein complexes within small organelles throughout dendrites 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 AMPARs at excitatory synapses. Immunoprecipitation revealed that NSG2 physically interacts with both the GluA1 and GluA2 AMPAR subunits in mouse brain. Knockout of NSG2 in mouse hippocampal neurons selectively impaired the frequency of miniature excitatory postsynaptic currents (mEPSCs) and caused alterations in PSD95 expression at postsynaptic densities. 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.Significance Statement Due to their morphological and functional complexity, neurons have evolved specialized proteins like those of the neuron-specific gene family (NSG1-3). Important developmental and synaptic functions have been attributed to NSG1/NEEP21 and NSG3/Calcyon while the function of NSG2/HMP19/NVTA2 has remained uncharacterized. Here we show that NSG2 localizes to a large proportion of excitatory synapses, interacts with AMPARs, and modulates their surface expression during synaptogenesis. Alterations of NSG2 expression affected both the amplitude and frequency of excitatory neurotransmission that is not compensated for by other NSG family members. Thus, NSG2 appears critical for excitatory synapse formation and/or maintenance and forced expression can promote increased synaptic efficacy. %U https://www.eneuro.org/content/eneuro/early/2019/01/04/ENEURO.0292-18.2018.full.pdf