Loss of ARHGAP15 affects the directional control of migrating interneurons in the embryonic cortex and increases susceptibility to epilepsy

• DOI: 10.3389/fcell.2022.875468
• Publication Date: 2022-12-08T14:52:01Z
• Authors: Carla Liaci; Mattia Camera; Valentina Zamboni; Gabriella Sarò; Alessandra Ammoni; Elena Parmigiani; Luisa Ponzoni; Enis Hidisoglu; Giuseppe Chiantia; Andrea Marcantoni; Maurizio Giustetto; Giulia Tomagra; Valentina Carabelli; Federico Torelli; Mariaelvina Sala; Yuchio Yanagawa; Kunihiko Obata; Emilio Hirsch; Giorgio R. Merlo
• Keywords: Synaptogenesis

GTPases of the Rho family are components signaling pathways linking extracellular signals to control cytoskeleton dynamics. Among these, RAC1 plays key roles during brain development, ranging from neuronal migration neuritogenesis, synaptogenesis, and plasticity. activity is positively negatively controlled by guanine nucleotide exchange factors (GEFs), guanosine dissociation inhibitors (GDIs), GTPase-activating proteins (GAPs), but specific role each regulator in vivo poorly known. ARHGAP15 a RAC1-specific GAP expressed development fraction migrating cortical interneurons (CINs) majority adult CINs. During loss causes altered directionality leading process tangentially CINs, along with morphology vitro. Likewise, time-lapse imaging embryonic CINs revealed coordinated directional radial migration, possibly due hyper-exploratory behavior. In cortex, observed defects lead subtle alteration distribution CALB2-, SST-, VIP-positive interneurons. Adult Arhgap15-knock-out mice also show reduced intrinsic excitability, spontaneous subclinical seizures, increased susceptibility pro-epileptic drug pilocarpine. These results indicate that imposes fine negative regulation on required for morphological maturation CIN consequences their laminar inhibitory function.