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

Edison Leung; Ethan W. Lau; Andi Liang; Constanza de Dios; Robert Suchting; Linda Östlundh; Joseph C. Masdeu; Masahiro Fujita; Marsal Sanches; Jair C. Soares; Sudhakar Selvaraj

doi:10.1038/s41380-021-01410-9

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

Edison Leung, Ethan W. Lau, Andi Liang, Constanza de Dios, Robert Suchting, Linda Östlundh, Joseph C. Masdeu, Masahiro Fujita, Marsal Sanches, Jair C. Soares, Sudhakar Selvaraj

Research output: Contribution to journal › Review article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	1362-1372
Number of pages	11
Journal	Molecular Psychiatry
Volume	27
Issue number	3
DOIs	https://doi.org/10.1038/s41380-021-01410-9
State	Published - Mar 2022

Keywords

Bipolar Disorder
Brain
Depressive Disorder, Major/genetics
Disks Large Homolog 4 Protein/genetics
Humans
Mood Disorders
RNA, Messenger

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

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10.1038/s41380-021-01410-9

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Leung, E., Lau, E. W., Liang, A., de Dios, C., Suchting, R., Östlundh, L., Masdeu, J. C., Fujita, M., Sanches, M., Soares, J. C., & Selvaraj, S. (2022). Alterations in brain synaptic proteins and mRNAs in mood disorders: a systematic review and meta-analysis of postmortem brain studies. Molecular Psychiatry, 27(3), 1362-1372. https://doi.org/10.1038/s41380-021-01410-9

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

abstract = "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.",

keywords = "Bipolar Disorder, Brain, Depressive Disorder, Major/genetics, Disks Large Homolog 4 Protein/genetics, Humans, Mood Disorders, RNA, Messenger",

author = "Edison Leung and Lau, {Ethan W.} and Andi Liang and {de Dios}, Constanza and Robert Suchting and Linda {\"O}stlundh and Masdeu, {Joseph C.} and Masahiro Fujita and Marsal Sanches and Soares, {Jair C.} and Sudhakar Selvaraj",

note = "Funding Information: 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 Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = mar,

doi = "10.1038/s41380-021-01410-9",

language = "English (US)",

volume = "27",

pages = "1362--1372",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Alterations in brain synaptic proteins and mRNAs in mood disorders

T2 - a systematic review and meta-analysis of postmortem brain studies

AU - Leung, Edison

AU - Lau, Ethan W.

AU - Liang, Andi

AU - de Dios, Constanza

AU - Suchting, Robert

AU - Östlundh, Linda

AU - Masdeu, Joseph C.

AU - Fujita, Masahiro

AU - Sanches, Marsal

AU - Soares, Jair C.

AU - Selvaraj, Sudhakar

N1 - Funding Information: 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 Information: 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. Funding Information: 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. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022/3

Y1 - 2022/3

N2 - 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.

AB - 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.

KW - Bipolar Disorder

KW - Brain

KW - Depressive Disorder, Major/genetics

KW - Disks Large Homolog 4 Protein/genetics

KW - Humans

KW - Mood Disorders

KW - RNA, Messenger

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U2 - 10.1038/s41380-021-01410-9

DO - 10.1038/s41380-021-01410-9

M3 - Review article

C2 - 35022529

AN - SCOPUS:85122763438

VL - 27

SP - 1362

EP - 1372

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 3

ER -

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

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Keywords

ASJC Scopus subject areas

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