Investigating the role of SNX27-retromer in excitatory/inhibitory balance in health and disease

Maintaining the delicate balance between excitatory and inhibitory synaptic activity is crucial for proper brain function. The endosomal trafficking complex, retromer, plays a pivotal role in synaptic function by regulating the post-endocytic sorting of a variety of integral proteins at both excitatory and inhibitory synapses. As a result, SNX27/retromer is emerging as a potential mediator of excitatory/inhibitory crosstalk. In surface proteomic screens from primary cultured neurons, we have shown that a variety of subunits of γ-aminobutyric acid receptors (GABAARs) exhibit reduced surface expression in response to knockdown of SNX27, or the core retromer component Vps35. Furthermore, GABAA receptors co-immunoprecipitate with SNX27 from cultured neurons. Our findings indicate that GABAARs are cargos of the SNX27/retromer complex, furthering our understanding of the roles of SNX27/retromer at inhibitory synapses. We are now expanding this work to understand the role of SNX27/retromer in targeting of GABAARs to synaptic sites, how this process may be regulated by neuronal activity, and its potential implication in disease states.