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Brain-wide changes in excitation-inhibition balance of major depressive disorder: a systematic review of topographic patterns of GABA- and glutamatergic alterations

Molecular Psychiatry volume 28, pages 3257–3266 (2023)Cite this article

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Abstract

The excitation-inhibition (E/I) imbalance is an important molecular pathological feature of major depressive disorder (MDD) as altered GABA and glutamate levels have been found in multiple brain regions in patients. Healthy subjects show topographic organization of the E/I balance (EIB) across various brain regions. We here raise the question of whether such EIB topography is altered in MDD. Therefore, we systematically review the gene and protein expressions of inhibitory GABAergic and excitatory glutamatergic signaling-related molecules in postmortem MDD brain studies as proxies for EIB topography. Searches were conducted through PubMed and 45 research articles were finally included. We found: i) brain-wide GABA- and glutamatergic alterations; ii) attenuated GABAergic with enhanced glutamatergic signaling in the cortical-subcortical limbic system; iii) that GABAergic signaling is decreased in regions comprising the default mode network (DMN) while it is increased in lateral prefrontal cortex (LPFC). These together demonstrate abnormal GABA- and glutamatergic signaling-based EIB topographies in MDD. This enhances our pathophysiological understanding of MDD and carries important therapeutic implications for stimulation treatment.

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Fig. 1: PRISMA flow chart.
Fig. 2: Global excitation-inhibition balance changes in the postmortem MDD brain.
Fig. 3: Excitation-inhibition imbalance in cortical-subcortical limbic regions of the postmortem MDD brain.
Fig. 4: Excitation-inhibition imbalance in default mode and lateral prefrontal regions of the postmortem MDD brain.
Fig. 5: Diagram of the key observations.

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Acknowledgements

The authors thank Dr. Dick Swaab (Netherlands Institute for Neuroscience) for his academic advice on this work. There is no funding support for this research.

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Authors and Affiliations

  1. Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yu-Ting Hu, Zhong-Lin Tan & Georg Northoff

  2. Institute of Mental Health Research, University of Ottawa, Ottawa, Canada

    Yu-Ting Hu & Georg Northoff

  3. Central Institute of Mental Health, Heidelberg University, Mannheim, Germany

    Dusan Hirjak

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Y.H. and G.N. designed the study. Y.H. and Z.T. contributed to the reference retrieval. Y.H. and G.N. made the figures. Y.H., Z.T., D.H., and G.N. wrote the manuscript.

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Correspondence to Yu-Ting Hu or Georg Northoff.

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Hu, YT., Tan, ZL., Hirjak, D. et al. Brain-wide changes in excitation-inhibition balance of major depressive disorder: a systematic review of topographic patterns of GABA- and glutamatergic alterations. Mol Psychiatry 28, 3257–3266 (2023). https://doi.org/10.1038/s41380-023-02193-x

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