Neuronal ARHGAP8 controls synapse structure and AMPA receptor-mediated synaptic transmission

The aberrant formation and function of neuronal synapses are recognized as major phenotypes in many cases of neurodevelopmental (NDDs) and -psychiatric disorders (NPDs). A growing body of research has identified an expanding number of susceptibility genes encoding proteins with synaptic function. Here, we present the first brain-focused characterization of a potential new susceptibility gene, ARHAGP8, which encodes a Rho GTPase activating protein (RhoGAP). Accumulating evidence suggests that ARHGAP8 plays a pivotal role in the pathogenesis of NPDs/NDDs. We provide the first evidence for ARHGAP8 as a novel player at excitatory synapses, with its synaptic localisation linked to the presence of the developmentally important NMDA receptor subunit GluN2B. By increasing ARHGAP8 levels in hippocampal neurons to mimic elevated levels found in subsets of patients, we observed reductions in dendritic complexity and spine volume, accompanied by a significant decrease in synaptic AMPA receptor-mediated transmission. These results suggest that ARHGAP8 plays a role in shaping the morphology and function of excitatory synapses, and prompt further investigation of ARHGAP8 as a candidate gene in NDDs/NPDs.