Abstract
The signaling scaffold protein GIT1 is expressed widely throughout the brain, but its function in vivo remains elusive. Mice lacking GIT1 have been proposed as a model for attention deficit-hyperactivity disorder, due to alterations in basal locomotor activity as well as paradoxical locomotor suppression by the psychostimulant amphetamine. Since we had previously shown that GIT1-knockout mice have normal locomotor activity, here we examined GIT1-deficient mice for ADHD-like behavior in more detail, and find neither hyperactivity nor amphetamine-induced locomotor suppression. Instead, GIT1-deficient mice exhibit profound learning and memory defects and reduced synaptic structural plasticity, consistent with an intellectual disability phenotype. We conclude that loss of GIT1 alone is insufficient to drive a robust ADHD phenotype in distinct strains of mice. In contrast, multiple learning and memory defects have been observed here and in other studies using distinct GIT1-knockout lines, consistent with a predominant intellectual disability phenotype related to altered synaptic structural plasticity.
Highlights
The GRK-interacting (GIT) proteins, GIT1 and GIT2, are signaling adaptor proteins that function as GTPase-activating proteins (GAPs) for the ADP-ribosylation factor (Arf) small GTP-binding proteins [1, 2]
Rather than hyperactivity, GIT1 KO mice exhibited reduced spontaneous locomotor activity in the dark phase at some time points (Fig 1A), but when activity was measured as total distance traveled, GIT1 KO activity was statistically indistinguishable from that of wildtype littermates during the dark or the light phases (Fig 1B, 1C and 1D)
We tested the effect of amphetamine administration during the dark phase of the diurnal cycle, and found that a high dose of 4 mg/kg amphetamine greatly increased locomotor activity of young GIT1 KO mice as well as of control wildtype mice (Fig 2A)
Summary
The GRK-interacting (GIT) proteins, GIT1 and GIT2, are signaling adaptor proteins that function as GTPase-activating proteins (GAPs) for the ADP-ribosylation factor (Arf) small GTP-binding proteins [1, 2]. GIT1 regulates synaptic structural plasticity underlying learning exchange factors (GEFs) that activate the p21 Rac1/Cdc small GTP-binding proteins and scaffold the conventional p21-activated kinases (PAKs 1–3) [7]. The GIT/PIX complex is recruited to specific cellular locations in response to extracellular signals, including to both pre-synaptic and post-synaptic neuronal membranes [8,9,10,11,12]. At these locations, GIT/PIX complexes function to regulate Arf and Rac1/Cdc signaling, and as scaffolds for a large number of signaling partners, but importantly including PAKs [2]
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