A Critical Role of GIT1 in Vertebrate and Invertebrate Brain Development

GIT1, a multifunctional signaling adaptor protein, is implicated in the development of dendritic spines and neuronal synapses. GIT1 forms a signaling complex with PIX, RAC, and PAK proteins that is known to play important roles in brain development. Here we found that Git1-knockout (Git1-/-) mice show a microcephaly-like small brain phenotype, which appears to be caused by reduced neuronal size rather than number. Git1-/- mice also show decreased dendritic spine number without morphological alterations in the hippocampus. Behaviorally, Git1-/- mice show impaired motor coordination and learning and memory. In addition, adult dGit Drosophila mutants show decreased brain size and abnormal morphology of the mushroom body. These results suggest that GIT1 is important for brain development in both rodents and flies.

Aberrant Thalamocortical Synchrony Associated with Behavioral Manifestations in Git1-/- Mice

Cross-talk between the thalamus and cortex has been implicated in attention but its pathogenic role in attention-deficit/hyperactivity disorder (ADHD) remains unknown. Here, I demonstrate that Git1-/- mice, previously proposed as an animal model for ADHD, show abnormal theta oscillation in the thalamus. Multi-electrode recordings revealed that Git1-/- mice have hyper-synchrony of neural activities between the thalamus and cortex. The abnormal thalamic oscillation and thalamocortical synchrony in Git1-/- mice were markedly reduced by amphetamine. In addition, ethosuximide ameliorates abnormal thalamic oscillation and ADHD-like hyperactivity shown in Git1-/- mice. My study suggests critical roles of GIT1 and thalamocortical neural circuitry in ADHD.