Disruption of ArhGAP15 results in hyperactive Rac1, affects the architecture and function of hippocampal inhibitory neurons and causes cognitive deficits

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.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…The genetic ablation of Arhgap15 in the mouse hippocampus leads to decreased complexity of the dendritic tree of neurons. Moreover, cultured hippocampal neurons from rat embryos knocked down for Arhgap15 have fewer spines, although the morphology of these spines is not changed compared to control neurons 279 . ARHGAP15 was linked to ASD in a case study of a young man with marked intellectual disability.…”

“…Rac1 with which it interacts through its C-terminus domain 279,280 . It has also been shown to interact with the Rac1 downstream effectors PAK1/2 via its N-terminus ( Figure 6).…”

Mib1 contributes to persistent directional cell migration by regulating the Ctnnd1-Rac1 pathway

“…Defects in the genes encoding these regulators affect Rac1 activity. For example, ArhGAP15 is one of the Rac1 GAPs and is required for negative regulation of Rac1 activity; its defect induces elevated Rac1 activity and affects directional migration of hippocampal interneurons in the mouse (39). Another level of Rac1 regulation is achieved by Ctnnd1.…”

Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks

“…Taken together, the link between ZEB2 and neurological development and phenotypes makes ZEB2 a plausible candidate gene for schizophrenia. On the other hand, mice mutants for the ARHGAP15 gene showed cognitive deficits due to impaired neuritogenesis in the hippocampus [54], and a de novo synonymous mutation in this gene was found in a patient with sporadic autism [55], followed by a recent report of a chromatin interaction of a schizophrenia GWAS locus with the promoter of the ARHGAP15 gene [8].…”