Hyper-activation of the Rho-GTPase Rac1 via disruption of ArhGAP15 results in reduced architectural and functional complexity

The Rho-type small GTPases (Rho, Rac and cdc42) are components of complex signal transduction pathways that link extracellular environmental cues with the control of cytoskeletal dynamic. During brain development, Rac1 plays essential roles ranging from chemotaxis and neuronal migration to neuritogenesis, synapsis formation and plasticity. Rac1 activity is positively and negatively controlled by several molecules, however the role of each specific regulators is poorly known. We have generated mice null for ArhGAP15, a Rac1-specific GTPase-activating protein expressed in embryonic migrating interneurons and in a large fraction of both excitatory and inhibitory neurons of the adult cortex and hippocampus. Loss of ArhGAP15 results in hyper-activation of Rac1 in the embryonic and adult forebrain, and increased retrograde actin dynamic at the growth cone, associated with defects in neuronal migration, reduced neuritogenesis and reduced spine formation. In spite of a nearly normal cyto-architecture and cortical layering, EEG spectral analysis show reduced high-frequency activity, increased lower frequencies activity, and overall reduced variability. Furthermore, multi-electrode array recordings of spontaneous activity of cultured primary neurons from ArhGAP15 KO cortex and hippocampus show delayed onset, reduced amplitude, reduced variability and inability to synchronize. Finally we observe motor hyperactivity. Thus a fine modulation of Rac1 activity is required for attaining a proper architecture and function of cortical and hippocampal circuits, and its hyper-activation leads to an Alzheimer spectrum phenotype.