Excitatory-inhibitory balance in adolescents at high genetic risk of mental disorder: a study of cortical gamma oscillations and GABA concentrations in 22q11.2 deletion syndrome. (360G-Wellcome-102003_Z_13_Z)

Neurodevelopmental disorders such as schizophrenia, autism and ADHD share clinical features, environmental risk factors and show familial co-aggregation. Recent genetic findings suggest that both common and rare genetic variants confer susceptibility across this spectrum of disorders, suggesting common pathogenic mechanisms. Cortical excitatory-inhibitory imbalance is proposed as one potential mechanism for the increased risk of mental disorder across traditional diagnostic boundaries. Marker s of disturbance in this balance include gamma oscillations (measured by magnetoencephalography, MEG) and GABA concentrations (measured by MRS). These markers have been shown to be abnormal in idiopathic schizophrenia, autism and ADHD. The 22q11.2 deletion is one of the strongest known genetic risk factors for mental disorder. I propose to use MEG and MRS to investigate cortical gamma oscillations and GABA concentrations in a sample of adolescents with 22q11.2 deletion syndrome and a sample o f unaffected siblings. I will conduct between-group analyses to determine whether the 22q11.2 deletion is associated with abnormal gamma oscillatory activity and GABA concentrations in the cortex. I will also investigate the relationship between gamma oscillations, GABA concentrations and psychopathology in 22q11.2DS. To my knowledge, this will be the first study of gamma oscillations and GABA concentrations in this high-risk group.