Hippocampal neuroanatomy in first episode psychosis: A putative role for glutamate and serotonin receptors,Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Hippocampal neuroanatomy in first episode psychosis: A putative role for glutamate and serotonin receptors
Progress in Neuro-Psychopharmacology and Biological Psychiatry ( IF 5.3 ) Pub Date : 2021-03-07 , DOI: 10.1016/j.pnpbp.2021.110297
Min Tae M Park ₁ , Peter Jeon ₂ , Ali R Khan ₃ , Kara Dempster ₁ , M Mallar Chakravarty ₄ , Jason P Lerch ₅ , Michael MacKinley ₆ , Jean Théberge ₇ , Lena Palaniyappan ₈

Affiliation

Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Canada.
Department of Medical Biophysics, Western University, London, Canada.
Department of Medical Biophysics, Western University, London, Canada; Robarts Research Institute, Western University, London, Canada.
Departments of Psychiatry and Biological and Biomedical Engineering, McGill University, Montreal, Canada; Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Canada.
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.
Robarts Research Institute, Western University, London, Canada.
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.
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.

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.

中文翻译：

首发精神病中的海马神经解剖学：谷氨酸和血清素受体的推定作用

5-羟色胺能和谷氨酸能信号的破坏相互作用并促成精神分裂症的病理生理学，这与海马体特别相关，其中注意到血清素受体的不同表达。海马萎缩是精神分裂症的一个公认特征，由于谷氨酸受体密度的变化，选定的亚区被假设为特别脆弱。我们利用 4 个数据源研究了首发精神病 (FEP) 中与受体分布相关的海马异常：(1) 超高场 (7-Tesla) 结构神经成像，和 (2) 质子磁共振波谱 (1H-来自 27 名健康和 41 名 FEP 受试者的谷氨酸 MRS)，(3) 来自 Allen 人脑图谱的基因表达数据和 (4) 血清素受体系统图谱。自动化方法描绘了海马体，以绘制跨子域的受体密度图。我们使用基因表达数据来关联海马中的血清素和谷氨酸受体基因。个体海马形状受体排列的测量是通过规范建模和与受体分布的相关性得出的，称为受体特异性形态特征 (RSMS)。我们发现 FEP 中的海马体积减少，而 CA4 齿状回的减少最大。基因表达表明 5-HT1A 和 5-HT4 分别与 AMPA 和 NMDA 表达相关。FEP 中子场体积减小的幅度与 5-HT1A 最相关（个体海马形状受体排列的测量是通过规范建模和与受体分布的相关性得出的，称为受体特异性形态特征 (RSMS)。我们发现 FEP 中的海马体积减少，而 CA4 齿状回的减少最大。基因表达表明 5-HT1A 和 5-HT4 分别与 AMPA 和 NMDA 表达相关。FEP 中子场体积减小的幅度与 5-HT1A 最相关（个体海马形状受体排列的测量是通过规范建模和与受体分布的相关性得出的，称为受体特异性形态特征 (RSMS)。我们发现 FEP 中的海马体积减少，而 CA4 齿状回的减少最大。基因表达表明 5-HT1A 和 5-HT4 分别与 AMPA 和 NMDA 表达相关。FEP 中子场体积减小的幅度与 5-HT1A 最相关（R = 0.64, p = 4.09E-03) 和 5-HT4 ( R = 0.54, p = 0.02) 密度与预期一致，并使用先前公布的两项 FEP 研究的数据进行了复制。右侧 5-HT4-RSMS 与 MRS 谷氨酸相关 ( R = 0.357, p = 0.048)。我们通过血清素受体密度门控机制证明了推定的 FEP 中谷氨酸驱动的海马变异性，从而概述了血清素和谷氨酸之间在确定精神分裂症海马形态方面的机制相互作用。

更新日期：2021-03-19

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