Hyperactivity of Rac1 GTPase pathway affects the development of cortical inhibitory neurons

Small GTPases of the Rho family are key components of signaling pathways linking extracellular signals to cellular responses by the control of actin cytoskeleton dynamics. Among these, Rac1 plays key roles during brain development, ranging from chemotaxis and neuronal migration to neuritogenesis, synaptogenesis and plasticity. Rac1 activity is positively and negatively controlled by GEFs and GAPs, respectively, however the role of each regulator in vivo is poorly known. The GTPase-activating protein ArhGAP15 is a brain-specific negative regulator of Rac1, expressed during development in migrating cortical and hippocampal interneurons (INs) and in a fraction of most subtypes of adult cortical and hippocampal GABAergic INs. In the developing cortex, loss of ArhGAP15 results in reduced neuronal morphological complexity and altered control of directionality during tangential and radial migrations. Time-lapse videos of migrating GAD67-GFP+ cortical INs, during late development, show an exuberant extension and retraction of leading edges, suggesting an overphysiological exploratory behavior, which results in an inefficient reorientation. In the cortex of adult ArhGAP15-/- mice, migration defects lead to mild alterations of laminar distribution of Calretinin+ and Somatostatin+ IN subtypes, hyperexcitability of pyramidal neurons, spontaneous subclinical seizures and increased susceptibility to the pro-epileptic drug pilocarpine. Overall, these results indicate that ArhGAP15 participates in a fine negative regulation of the Rac1 GTPase, required for the control of INs orientation during cortical migration and for the maintenance of the excitatory/inhibitory balance.