Excitatory/Inhibitory Imbalance Underlies Hippocampal Atrophy in Individuals With 22q11.2 Deletion Syndrome With Psychotic Symptoms

Valentina Mancini; Muhammad G Saleh; Farnaz Delavari; Joëlle Bagautdinova; Stephan Eliez

doi:10.1016/j.biopsych.2023.03.021

Excitatory/Inhibitory Imbalance Underlies Hippocampal Atrophy in Individuals With 22q11.2 Deletion Syndrome With Psychotic Symptoms

Biol Psychiatry. 2023 Oct 1;94(7):569-579. doi: 10.1016/j.biopsych.2023.03.021. Epub 2023 Apr 1.

Authors

Valentina Mancini¹, Muhammad G Saleh², Farnaz Delavari³, Joëlle Bagautdinova³, Stephan Eliez⁴

Affiliations

¹ Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland. Electronic address: valentina.mancini@unige.ch.
² Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
³ Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland.
⁴ Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva School of Medicine, Geneva, Switzerland.

PMID: 37011759
DOI: 10.1016/j.biopsych.2023.03.021

Abstract

Background: Abnormal neurotransmitter levels have been reported in individuals at high risk for schizophrenia, leading to a shift in the excitatory/inhibitory balance. However, it is unclear whether these alterations predate 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 genetic risk for psychosis.

Methods: Glx (glutamate+glutamine) and GABA+ (gamma-aminobutyric acid with macromolecules and homocarnosine) concentrations were estimated in the anterior cingulate cortex, superior temporal cortex, and hippocampus using the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and the Gannet toolbox in 52 deletion carriers and 42 control participants. T1-weighted images were acquired longitudinally and processed with FreeSurfer version 6 to extract hippocampal volume. Subgroup analyses were conducted in deletion carriers with psychotic symptoms.

Results: While no differences were found in the anterior cingulate cortex, deletion carriers had higher levels of Glx in the hippocampus and superior temporal cortex and lower levels of GABA+ in the hippocampus than control participants. We additionally found a higher Glx concentration in the hippocampus of deletion carriers with psychotic symptoms. Finally, more pronounced hippocampal atrophy was significantly associated with increased Glx levels in deletion carriers.

Conclusions: We provide 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. These results are in line with theories proposing abnormally enhanced glutamate levels as a mechanistic explanation for hippocampal atrophy via excitotoxicity. Our results highlight a central role of glutamate in the hippocampus of individuals at genetic risk for schizophrenia.

Keywords: Development; GABA; Glutamate; Hippocampus; MRS; Schizophrenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Atrophy
DiGeorge Syndrome* / complications
DiGeorge Syndrome* / diagnostic imaging
DiGeorge Syndrome* / genetics
Glutamic Acid
Glutamine
Hippocampus / diagnostic imaging
Humans
Neurodegenerative Diseases*
Psychotic Disorders* / diagnostic imaging
Psychotic Disorders* / genetics
gamma-Aminobutyric Acid

Substances

Glutamine
Glutamic Acid
gamma-Aminobutyric Acid