Hippocampal neuroanatomy in first episode psychosis: A putative role for glutamate and serotonin receptors

Min Tae M Park; Peter Jeon; Ali R Khan; Kara Dempster; M Mallar Chakravarty; Jason P Lerch; Michael MacKinley; Jean Théberge; Lena Palaniyappan

doi:10.1016/j.pnpbp.2021.110297

Hippocampal neuroanatomy in first episode psychosis: A putative role for glutamate and serotonin receptors

Prog Neuropsychopharmacol Biol Psychiatry. 2021 Aug 30:110:110297. doi: 10.1016/j.pnpbp.2021.110297. Epub 2021 Mar 7.

Authors

Min Tae M Park¹, Peter Jeon², Ali R Khan³, Kara Dempster¹, M Mallar Chakravarty⁴, Jason P Lerch⁵, Michael MacKinley⁶, Jean Théberge⁷, Lena Palaniyappan⁸

Affiliations

¹ Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Canada.
² Department of Medical Biophysics, Western University, London, Canada.
³ Department of Medical Biophysics, Western University, London, Canada; Robarts Research Institute, Western University, London, Canada.
⁴ Departments of Psychiatry and Biological and Biomedical Engineering, McGill University, Montreal, Canada; Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Canada.
⁵ Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁶ Robarts Research Institute, Western University, London, Canada.
⁷ Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Canada; Department of Medical Biophysics, Western University, London, Canada; Lawson Health Research Institute, London, Canada.
⁸ Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Canada; Robarts Research Institute, Western University, London, Canada; Lawson Health Research Institute, London, Canada. Electronic address: lpalaniy@uwo.ca.

PMID: 33691200
DOI: 10.1016/j.pnpbp.2021.110297

Abstract

Disrupted serotonergic and glutamatergic signaling interact and contribute to the pathophysiology of schizophrenia, which is particularly relevant for the hippocampus where diverse expression of serotonin receptors is noted. Hippocampal atrophy is a well-established feature of schizophrenia, with select subfields hypothesized as particularly vulnerable due to variation in glutamate receptor densities. We investigated hippocampal anomalies in first-episode psychosis (FEP) in relation to receptor distributions by leveraging 4 sources of data: (1) ultra high-field (7-Tesla) structural neuroimaging, and (2) proton magnetic resonance spectroscopy (1H-MRS) of glutamate from 27 healthy and 41 FEP subjects, (3) gene expression data from the Allen Human Brain Atlas and (4) atlases of the serotonin receptor system. Automated methods delineated the hippocampus to map receptor density across subfields. We used gene expression data to correlate serotonin and glutamate receptor genes across the hippocampus. Measures of individual hippocampal shape-receptor alignment were derived through normative modelling and correlations to receptor distributions, termed Receptor-Specific Morphometric Signatures (RSMS). We found reduced hippocampal volumes in FEP, while CA4-dentate gyrus showed greatest reductions. Gene expression indicated 5-HT1A and 5-HT4 to correlate with AMPA and NMDA expression, respectively. Magnitudes of subfield volumetric reduction in FEP correlated most with 5-HT1A (R = 0.64, p = 4.09E-03) and 5-HT4 (R = 0.54, p = 0.02) densities as expected, and replicated using previously published data from two FEP studies. Right-sided 5-HT4-RSMS was correlated with MRS glutamate (R = 0.357, p = 0.048). We demonstrate a putative glutamate-driven hippocampal variability in FEP through a serotonin receptor-density gated mechanism, thus outlining a mechanistic interplay between serotonin and glutamate in determining the hippocampal morphology in schizophrenia.

Keywords: Glutamate; MRI; MRS; Schizophrenia; Serotonin.

Publication types

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

MeSH terms

Adult
Antipsychotic Agents / therapeutic use
Atrophy / pathology
Brain / pathology
Female
Glutamic Acid*
Hippocampus / pathology*
Humans
Male
Neuroanatomy*
Proton Magnetic Resonance Spectroscopy
Psychotic Disorders / drug therapy
Psychotic Disorders / physiopathology*
Receptors, Serotonin*

Substances

Antipsychotic Agents
Receptors, Serotonin
Glutamic Acid