Human Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) Regulates Dendritic Morphogenesis

Disturbances of synaptic connectivity during perinatal and adolescent periods have been hypothesized to be related to the pathophysiology of schizophrenia. Rho guanine nucleotide exchange factor11 (ARHGEF11) is a specific guanine nucleotide exchange factors(GEF) for RhoA, which is a critical regulator of actin cytoskeleton dynamics and organization of dendritic spinesand inhibitor of spine maintenance. ARHGEF11 variants are reported to be associated with a higher risk for the onset of schizophrenia in a Japanese population; however, how ARHGEF11 contributes to the pathogenesis of schizophrenia in dendritic spinesis unknown. Therefore, we first studied the distribution, binding, and function of ARHGEF11 in the dendritic spinesof the rat cerebral cortex. After subcellular fractionation of the rat cerebral cortex, ARHGEF11 was detected with synaptophysinand post-synaptic density protein 95 (PSD-95) in the P2 fractions including synaptosomalfractions containing presynaptic and postsynaptic densityproteins. Endogenous ARHGEF11 was coimmunoprecipitated with synaptophysinor PSD-95. In cortical primary neurons at 28 days in vitro, immunostaining revealed that ARHGEF11 located in the dendritesand dendritic spinesand colocalized with PSD-95 and synaptophysin. Overexpression of exogenous ARHGEF11 significantly decreased the number of spines (p = 0.008). These results indicate that ARHGEF11 is likely to be associated with synaptic membranesand regulation of spine.