Critical Role of Rho Guanine Nucleotide Exchange Factor 4 in Brain Function.

Abstract

Although Rho guanine nucleotide exchange factor 4 (Arhgef4) is highly expressed in the brain, its function remains poorly understood. Our previous study showed that Arhgef4 negatively regulates excitatory postsynaptic regional activity. This study investigated the effects of Arhgef4 deletion in postnatal forebrain-specific knockout mice on brain function, synaptic proteins, and behaviors. We generated a knockout mouse with Arhgef4 deleted from the forebrain and analyzed gene expression and protein levels by RT-PCR and western blot. Synaptic function was assessed through electrophysiological recordings, and behavioral tests evaluated memory and anxiety. In these conditional knockout (cKO) mice, we observed a significant decrease in the expression of a 75-kDa brain-enriched isoform of Arhgef4 in the forebrain. In KO mice, pre- and post-synaptic protein levels were unchanged. However, in cultured hippocampal neurons from KO mice, the levels of postsynaptic density protein 95 (PSD-95) in the postsynaptic regions were significantly increased from the pre-mature stage to the fully mature stage during neuronal development. In contrast, the number of dendritic protrusions decreased during the early mature stage of the cultured neurons. Electrophysiological recordings of hippocampal neurons from KO mice showed a significant increase in miniature excitatory postsynaptic currents (mEPSC) frequency. Furthermore, Arhgef4 KO mice exhibited enhanced long-term memory and reduced anxiety-related behaviors. These findings suggest that Arhgef4 plays a role in regulating brain functions such as learning, memory, and anxiety.