Dysregulation of Rho GTPases in the αPix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits

Abstract

Mutations in the ARHGEF6 gene, encoding the guanine nucleotide exchange factor αPIX/Cool-2 for the Rho GTPases Rac1 and Cdc42, cause X-linked intellectual disability (ID) in humans. We show here that αPix/Arhgef6 is primarily expressed in neuropil regions of the hippocampus. To study the role of αPix/Arhgef6 in neuronal development and plasticity and gain insight into the pathogenic mechanisms underlying ID, we generated αPix/Arhgef6-deficient mice. Gross brain structure in these mice appeared to be normal; however, analysis of Golgi-Cox-stained pyramidal neurons revealed an increase in both dendritic length and spine density in the hippocampus, accompanied by an overall loss in spine synapses. Early-phase long-term potentiation was reduced and long-term depression was increased in the CA1 hippocampal area of αPix/Arhgef6-deficient animals. Knockout animals exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations, suggesting that this model mimics the human ID phenotype. The structural and electrophysiological alterations in the hippocampus were accompanied by a significant reduction in active Rac1 and Cdc42, but not RhoA. In conclusion, we suggest that imbalance in activity of different Rho GTPases may underlie altered neuronal connectivity and impaired synaptic function and cognition in αPix/Arhgef6 knockout mice.

Dileucine and PDZ-binding Motifs Mediate Synaptic Adhesion-like Molecule 1 (SALM1) Trafficking in Hippocampal Neurons

“…Loss of the ␣PIX/ARHGEF6 gene, the guanine nucleotide exchange factor for the Rho GTPases Rac1 and Cdc42, causes X-linked mental retardation in humans. In knock-out mice, there is a loss of functional synapses, identified by EM and a decrease in longterm potentiation (60). Therefore, one possible mechanism for the formation of filopodia by mutant SALM1 is that the increased surface expression of SALM1 L700A may transduce a signal to the actin cytoskeleton that promotes filopodia growth.…”

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

“…Indeed, loss of GIT1 in three distinct knockout mice strains leads to severe defects in learning and memory (Schmalzigaug et al, 2009a;Menon et al, 2010;Won et al, 2011;Hong and Mah, 2015), similar to the cognitive defects in mice that lack α-PIX (Ramakers et al, 2012), or in PAK1/PAK3-double-knockout mice . Cognitive functions in GIT2-or β-PIX-deficient mice have not been reported but GIT2-knockout mice exhibit anxiety-like behavior (Schmalzigaug et al, 2009b).…”

“…GIT and PIX proteins act as key regulators of spine morphology and synapse formation (see Frank and Hansen, 2008). Mice deficient in GIT1 have reduced dendritic spine density in vivo (Menon et al, 2010), whereas α-PIXdeficient mice show increased spine density with an increase in spine length and branching (Ramakers et al, 2012). There are no reports of the effects of GIT2 or β-PIX knockout on dendritic spines in vivo.…”

RacGAP α2-Chimaerin Function in Development Adjusts Cognitive Ability in Adulthood

“…The molecular bases for this process are not well understood. Recent evidence obtained primarily from studies of developmental psychiatric disorders, such as autism spectrum disorders (ASDs) and schizophrenia, suggests that Rho family small guanosine triphosphatases (Rho GTPases) and their regulators could be involved in this process (Ba et al, 2013;Cahill et al, 2009;Carlson et al, 2011;Ramakers et al, 2012;van Bokhoven, 2011). Rho GTPases, such as RhoA, Rac, and Cdc42, are key regulators of actin dynamics, and they are activated by Rho guanine nucleotide exchange factors (GEFs) and inactivated by Rho GTPase-activating proteins (GAPs) (Luo, 2000).…”