Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility
The molecular and cellular basis of cognitive deficits in schizophrenia remains poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically. Towards this goal, CGM Investigator Steve Haggarty and colleagues studied the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. Profiling GIT1 knockout mice revealed memory deficits and reduced cortical dendritic spine density. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion perturbs specific networks of synaptic proteins, suggesting that GIT1 regulates the phosphorylation of critical regulators of neuroplasticity.