Excitatory inhibitory imbalance underlies hippocampal atrophy in individuals with 22q11.2 Deletion Syndrome with psychotic symptoms

BackgroundAbnormal neurotransmitter levels have been reported in subjects at high risk for schizophrenia, leading to a shift in the excitatory/inhibitory balance. However, it is unclear if these alterations are predating the onset of clinically relevant symptoms. Our aim was to explore in vivo measures of excitatory/inhibitory balance in 22q11.2 deletion carriers, a population at high genetic risk for psychosis.MethodsGlx (glutamate + glutamine) and GABA+ concentrations were estimated in the anterior cingulate cortex (ACC), superior temporal gyrus (STG) and hippocampus using a MEGAPRESS sequence and the Gannet toolbox in 52 deletion carriers and 42 controls. T1-weighted images were acquired longitudinally and processed with Freesurfer v.6.0 to extract hippocampal volume. Subgroup analyses were conducted in deletion carriers with psychotic symptoms identified by means of SIPS.ResultsWhile no differences were found in the ACC, deletion carriers had higher levels of Glx in the hippocampus and STG, and lower levels of GABA+ in the hippocampus compared to controls. We additionally found a higher Glx concentration in the hippocampus of psychotic compared to non-psychotic deletion carriers. Finally, more pronounced hippocampal atrophy and increased functional variability were both significantly associated with increased Glx levels in deletion carriers.ConclusionsThis study provides evidence for an excitatory/inhibitory imbalance in temporal brain structures of deletion carriers, with a further hippocampal Glx increase in individuals with psychotic symptoms that was associated with hippocampal atrophy and abnormal function. These results support theories proposing abnormally enhanced glutamatergic neural transmission as a mechanistic explanation for hippocampal atrophy via excitotoxicity. Overall, our results highlight a central role of glutamate in the hippocampus of individuals at genetic risk for schizophrenia.