Loss of RAC1 regulator ARHGEF6 results in defects in distribution and function of hippocampal interneurons

Intellectual disability (ID) is a disorder characterized by restricted intellectual function and adaptive behavior. It has been consistently associated with alterations in neuronal migration, neuritogenesis, synaptogenesis, and plasticity, thus impacting neuronal networks’ function leading to excitatory-inhibitory imbalance, a proposed unifying cellular phenotype. Those processes involve cytoskeleton dynamics and its complex regulatory apparatus. Key regulatory enzymes are the Rho GTPases, such as RAC1, which link extracellular stimuli with cytoskeleton dynamics. RAC1 activity is positively and negatively controlled by, respectively, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). However, the precise role of each regulator in vivo is not well understood. Different mutations in genes associated with ID lead to RAC1 pathway hypoactivity, including both its effectors and regulators. In particular, ARHGEF6 gene, coding for a RAC1 positive regulator, causes MRX46, a form of X-linked ID. Arhgef6-KO mouse model shows reduced RAC1 activity at hippocampal level, alterations in synaptic activity patterns, and behavioral impairments that recapitulate human ID. To study the role of ARHGEF6 in neuronal development in the context of hippocampal inhibitory interneurons, we crossed Arhgef6-KO with the GAD67-eGFP reporter strain and conducted morphological, electrophysiological, and molecular analyses. Defects in interneurons distribution and function have been observed in KO mice and are currently under investigation. Contextually, we are attempting to achieve a GTPase-specific, controlled re-modulation of RAC1 activity by testing in vitro a peptide designed to decrease the interaction between RAC1 and its endogenous inhibitors (i.e., GAP proteins). If successful, this could lead to a rescue of the normal phenotype in presence of Arhgef6 gene mutation.