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Alterations in brain synaptic proteins and mRNAs in mood disorders: a systematic review and meta-analysis of postmortem brain studies

Molecular Psychiatry volume 27, pages 1362–1372 (2022)Cite this article

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Abstract

The pathophysiological mechanisms underlying bipolar (BD) and major depressive disorders (MDD) are multifactorial but likely involve synaptic dysfunction and dysregulation. There are multiple synaptic proteins but three synaptic proteins, namely SNAP-25, PSD-95, and synaptophysin, have been widely studied for their role in synaptic function in human brain postmortem studies in BD and MDD. These studies have yielded contradictory results, possibly due to the small sample size and sourcing material from different cortical regions of the brain. We performed a systematic review and meta-analysis to understand the role of these three synaptic proteins and other synaptic proteins, messenger RNA (mRNA) and their regional localizations in BD and MDD. A systematic literature search was conducted and the review is reported in accordance with the MOOSE Guidelines. Meta-analysis was performed to compare synaptic marker levels between BD/MDD groups and controls separately. 1811 papers were identified in the literature search and screened against the preset inclusion and exclusion criteria. A total of 72 studies were screened in the full text, of which 47 were identified as eligible to be included in the systematic review. 24 of these 47 papers were included in the meta-analysis. The meta-analysis indicated that SNAP-25 protein levels were significantly lower in BD. On average, PSD-95 mRNA levels were lower in BD, and protein levels of SNAP-25, PSD-95, and syntaxin were lower in MDD. Localization analysis showed decreased levels of PSD-95 protein in the frontal cortex. We found specific alterations in synaptic proteins and RNAs in both BD and MDD. The review was prospectively registered online in PROSPERO international prospective register of systematic reviews, registration no. CRD42020196932.

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Fig. 1: PRISMA diagram for studies used in the meta-analysis and systematic review.
Fig. 2: Forest plot of synaptic markers in mood disorders.

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Acknowledgements

We thank Ms. Mariam Al Ahbabi at the National Medical Library, the United Arab Emirates University, for her strategic support in locating all full-text articles and for verifying the non-predatory status of all included papers.

Funding

SS has received grants/research support from NIH R21 (1R21MH119441-01A1) and SAMHSA (6H79FG000470-01M003). The University of Texas Health Science center at Houston (UTHealth) faculty research supplement funds (SS) were utilized for this study. The institution played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Author notes

  1. These authors contributed equally: Edison Leung, Ethan W. Lau, Andi Liang.

Authors and Affiliations

  1. McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Edison Leung, Ethan W. Lau, Andi Liang, Marsal Sanches, Jair C. Soares & Sudhakar Selvaraj

  2. Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Edison Leung, Constanza de Dios, Robert Suchting, Marsal Sanches, Jair C. Soares & Sudhakar Selvaraj

  3. The National Medical Library, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

    Linda Östlundh

  4. Houston Methodist Neurological Institute, Houston, TX, USA

    Joseph C. Masdeu

  5. Weill Cornell Medicine, New York, NY, USA

    Joseph C. Masdeu & Masahiro Fujita

  6. PET Core Facility, Houston Methodist Research Insitute, Houston, TX, USA

    Masahiro Fujita

Authors
  1. Edison Leung
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  2. Ethan W. Lau
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  3. Andi Liang
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  4. Constanza de Dios
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  5. Robert Suchting
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  6. Linda Östlundh
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  7. Joseph C. Masdeu
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  8. Masahiro Fujita
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  9. Marsal Sanches
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  11. Sudhakar Selvaraj
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Contributions

Conceptualization, EL, CD, and SS; data curation and search, EWL, AL, LÖ, and SS; formal analysis, EL, CD, and RS, SS; funding acquisition, SS; investigation, EL, JCS, and SS; methodology, EL, CD, RS, LÖ, and SS; project administration, EL and SS; software, LÖ; supervision, SS; writing, review, and editing, EL, CD, RS, JCM, MF, MS, LÖ, and SS. All authors have read and agreed to the published version of the paper.

Corresponding author

Correspondence to Sudhakar Selvaraj.

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Competing interests

JCS has received grants/research support from BMS, Forrest, J&J, Merck, Compass pathways, Stanley Medical Research Institute, NIH and has been a speaker for Pfizer and Abbott. SS has received speaking honoraria from Global Medical Education and honoraria from British Medical Journal Publishing Group; own shares at Flow Med Tech. Research support from Compass pathways, Liva Nova and Janssen. All the other authors have no competing interests to disclose.

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Leung, E., Lau, E.W., Liang, A. et al. Alterations in brain synaptic proteins and mRNAs in mood disorders: a systematic review and meta-analysis of postmortem brain studies. Mol Psychiatry 27, 1362–1372 (2022). https://doi.org/10.1038/s41380-021-01410-9

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