Impaired spine formation and learning in GPCR kinase 2 interacting protein-1 (GIT1) knockout mice

Abstract

The G-protein coupled receptor (GPCR)-kinase interacting proteins 1 and 2 (GIT1 and GIT2) are scaffold proteins with ADP-ribosylating factor GTPase activity. GIT1 and GIT2 control numerous cellular functions and are highly expressed in neurons, endothelial cells and vascular smooth muscle cells (VSMC). GIT1 promotes dendritic spine formation, growth and motility in cultured neurons, but its role in brain in vivo is unknown. By using global GIT1 knockout mice (GIT1 KO), we show that deletion of GIT1 results in markedly reduced dendritic length and spine density in the hippocampus by 36.7 % (p < 0.0106*) and 35.1% (p< 0.0028*) respectively compared to WT controls. This correlated with their poor adaptation to new environments as shown by impaired performance on tasks dependent on learning. We also studied the effect of GIT1 gene deletion on brain microcirculation. In contrast to findings in systemic circulation, GIT1 KO mice had an intact blood-brain barrier and normal regional cerebral blood flow as determined with radiotracers. Thus, our data suggest that GIT1 plays an important role in brain in vivo by regulating spine density involved in synaptic plasticity that is required for processes involved in learning. KeywordsG-protein coupled receptor kinase interacting protein 1, GIT1; spine formation; cytoskeleton dynamics; brain morphology; blood brain barrier; BBB

GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice

“…2b). GIT1 deficiency markedly affected survival; ~50% of Git1 −/− mice died postnatally, as reported previously 18,22 . Git1 −/− mice that survived weighed 60-70% that of wild-type (WT) mice and had a normal appearance.…”

“…In rodent brains, GIT1 regulates neurite outgrowth 13,14 , spine morphogenesis 15,16 , synapse formation 15-20 and synaptic receptor localization of the glutamate receptor AMPA 21 . Git1-null (Git1 −/− ) mice show impaired dendritic outgrowth, reduced spine density, impaired fear responses and reduced adaptation to new and changing environments 18,22 . GIT1 associates with huntingtin, a protein implicated in Huntington's disease 23 .…”

Association study of GIT1 gene with attention‐deficit hyperactivity disorder in Brazilian children and adolescents

“…Importantly, although Git1-knockout mice were susceptible to early postnatal death, survivors developed normally and did not show any gross anatomical abnormalities (Schmalzigaug et al 2009). In another study, the neurons of Git1-knockout mice exhibited decreased dendritic lengths and spine densities in the hippocampus (Menon et al 2009). Moreover, behavioural analysis showed that these mice adapt poorly to new or changing environments (Menon et al 2009).…”

“…In another study, the neurons of Git1-knockout mice exhibited decreased dendritic lengths and spine densities in the hippocampus (Menon et al 2009). Moreover, behavioural analysis showed that these mice adapt poorly to new or changing environments (Menon et al 2009). Won et al (2011) investigated 27 single nucleotide polymorphisms (SNPs) in the GIT1 gene; only the rs550818 polymorphism, located in intron 20, was associated with ADHD susceptibility in a sample of Korean children.…”

Principles Driving the Spatial Organization of Rho GTPase Signaling at Synapses

“…Interestingly, β-PIX also binds to PAK (p21 activated kinase) via an N-terminal SH3 domain (Mott et al 2005), suggesting that the GIT1/β-PIX/PAK complex can organize and regulate β-PIX GEF activity and the Rac-mediated activation of PAK. Loss of GIT1 in mice results in reduced dendritic arborization and spine density and in multiple Attention Deficit Hyperactivity Disorder (ADHD)-like behaviors (Won et al 2011;Menon et al 2010;Schmalzigaug et al 2009). Importantly, GIT1 SNPs (single nucleotide polymorphisms) that reduce GIT1 expression are associated with human ADHD (Won et al 2011).…”