title: 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.
authors: Department of Neurons and Networks, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.
authors: Ger J A
authors: GJ
authors: Ramakers
authors: David
authors: D
authors: Wolfer
authors: Georg
authors: G
authors: Rosenberger
authors: Kerstin
authors: K
authors: Kuchenbecker
authors: Hans-Jürgen
authors: HJ
authors: Kreienkamp
authors: Janine
authors: J
authors: Prange-Kiel
authors: Gabriele
authors: G
authors: Rune
authors: Karin
authors: K
authors: Richter
authors: Kristina
authors: K
authors: Langnaese
authors: Sophie
authors: S
authors: Masneuf
authors: Michael R
authors: MR
authors: Bösl
authors: Klaus-Dieter
authors: KD
authors: Fischer
authors: Harm J
authors: HJ
authors: Krugers
authors: Hans-Peter
authors: HP
authors: Lipp
authors: Elly
authors: E
authors: van Galen
authors: Kerstin
authors: K
authors: Kutsche
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000235:genetics*; D004195:Disease Models, Animal; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics*; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000235:genetics*; D064067:Rho Guanine Nucleotide Exchange Factors; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C576603:ARHGEF6 protein, human; C576604:Arhgef6 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D020741:rho GTP-Binding Proteins