Abstract
During brain development, the small GTPases Rac1/Rac3 play key roles in neuronal migration, neuritogenesis, synaptic formation and plasticity, via control of actin cytoskeleton dynamic. Their activity is positively and negatively regulated by GEFs and GAPs molecules, respectively. However their in vivo roles are poorly known. The ArhGAP15 gene, coding for a Rac-specific GAP protein, is expressed in both excitatory and inhibitory neurons of the adult hippocampus, and its loss results in the hyperactivation of Rac1/Rac3. In the CA3 and dentate gyrus (DG) regions of the ArhGAP15 mutant hippocampus the CR+, PV+ and SST+ inhibitory neurons are reduced in number, due to reduced efficiency and directionality of their migration, while pyramidal neurons are unaffected. Loss of ArhGAP15 alters neuritogenesis and the balance between excitatory and inhibitory synapses, with a net functional result consisting in increased spike frequency and bursts, accompanied by poor synchronization. Thus, the loss of ArhGAP15 mainly impacts on interneuron-dependent inhibition. Adult ArhGAP15−/− mice showed defective hippocampus-dependent functions such as working and associative memories. These findings indicate that a normal architecture and function of hippocampal inhibitory neurons is essential for higher hippocampal functions, and is exquisitely sensitive to ArhGAP15-dependent modulation of Rac1/Rac3.
Highlights
Of Rac[1] (Rac1N) in post-mitotic neurons leads to subtle migration, differentiation and connectivity defects affecting hippocampal inhibitory neurons and hilar mossy cells[9,10,11]
Gaining a deep knowledge of the specific action of each GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) of the Rho/Rac GTPases for neuronal migration, neuritogenesis and synaptogenesis is of considerable importance; much of our current knowledge is derived from the use of either dominant-negative or constitutively active Rac[1] mutant proteins, or from the analysis of mice with conditional Rac1/3 loss-of-function mutations[6,7,9,10,11]
First we determined the number of CR+neurons showing an angle deviating >20° from the tangent, and observed no difference (Fig. 3i). We considered only those neurons showing a leading process oriented with an angle deviating >20° relative to the tangent, and examined at least 50 neurons per genotype; in the absence of ArhGAP15 we detected a significant increase (41.4 ± 2.7° in WT; 54.5 ± 2.9° in ArhGAP15−/−; p = 0.003) of the mean angle with the tangent (Fig. 3j), indicating that immature ArhGAP15−/− CR+deviate more than the WT counterpart
Summary
Of Rac[1] (Rac1N) in post-mitotic neurons leads to subtle migration, differentiation and connectivity defects affecting hippocampal inhibitory neurons (interneurons, INs) and hilar mossy cells[9,10,11]. Morphology and activity of cortical and hippocampal INs are strongly affected by the combined Rac1N+/− and Rac3−/− mutations: hippocampal and DG principal cells are hyperexcitable and mice show spontaneous epilepsy, due to IN dysfunctions[11] These phenotypes suggest a model in which Rac1/3 activity is required for a positive regulation of cytoskeletal dynamic during migration, neuritogenesis and synaptogenesis. Genetic models of Rac1/3 loss-of-function may not fully elucidate the role of these GTPases in terms of misregulated activity; for instance, little is known about the effect of hyperactivation of Rac1/3, in vivo We address this question by examining the consequence of hyperactive Rac1/3 resulting from the depletion of ArhGAP15 in mice, in terms of neuronal migration, differentiation, organization, electrical functions and behavioural performance. ArhGAP15−/− mice show behavioural deficits similar to those seen in mice with Rac1/3 loss-of-function mutations
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