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Sex-specific changes in the hippocampal proteome of Negr1<sup>-/-</sup> mice: insight into the mechanisms of neuropsychiatric disorders.

Overview

Authors: Srirathi Muthuraman1, Mohan Jayaram1, Liisi Promet1, Toomas Jagomäe1, Arun Kumar Devarajan2, Andreas-Christian Hade3, Mari-Anne Philips1, Katyayani Singh1, Eero Vasar1
ORCID iDs: Srirathi Muthuraman, Katyayani Singh
  1. Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, Tartu, Estonia
  2. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
  3. Department of Pathological Anatomy and Forensic Medicine, University of Tartu, 19 Ravila Street, Tartu, 50411 Estonia
Institutions: University of Tartu (Estonia)
Journal: Biology of sex differences, volume 17, issue 1, article 96
Dates: received 23 November 2025; accepted 18 March 2026; published online 26 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s13293-026-00890-0 · PMID 41888955 · PMCID PMC13141394 · OpenAlex W7140503621
Open access: gold, a free copy (OpenAlex)
Status: data only (how the code is found and verified)
Categories: genetics / omics (modality), human (organism), mouse (organism), rat (organism), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions
Keywords: Negr1, Sex-difference, Neuropsychiatric disorder, Animal model, Proteomics, Sex-specific, Pvalb, PV, Hippocampus
MeSH: Cell Adhesion Molecules, Neuronal*, Hippocampus*, Mental Disorders*, Proteome*, Sex Characteristics*, Animals, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout (* major topic)
Topic: Neurogenesis and neuroplasticity mechanisms (Developmental Neuroscience, Neuroscience), according to OpenAlex
Funding: Estonian Research Foundation, the Estonian Research Council (PRG685 and PRG2544, TARISTU24-TK22)
Citations: not cited yet (Europe PMC); 73 references in the paper

Abstract

Background: Neuronal Growth Regulator 1 (NEGR1) is a cell adhesion molecule involved in hippocampal circuit development and function. Human genetic studies have identified NEGR1 variants as risk factors for a broad spectrum of neuropsychiatric disorders. These disorders often display sex-specific differences in prevalence, progression, and behavioral impairment, reflecting underlying maladaptive changes in neural circuitry. Findings from preclinical studies using Negr1−/− mice show several hippocampal-based behavioral and anatomical endophenotypes relevant to neuropsychiatric disorders. The hippocampus, a key region implicated in these disorders, exhibits sex-dependent anatomical features that may shape the functional impact of Negr1. However, the mechanisms driving these sex-specific characteristics have not yet been elucidated. Here, we uncover sex-specific molecular signatures and pathways associated with Negr1, using Negr1−/− mice, a genetically relevant animal model for neuropsychiatric risk.

Methods: We performed label-free quantitative proteomic analysis using eight replicates of hippocampi dissected from male and female wild-type, and Negr1−/− mice. Differentially abundant proteins were subjected to functional annotation for Gene Ontology and Protein-Protein interaction using STRING analysis. NEGR1 cellular localization was examined by immunofluorescent in rat brain and human hippocampal sections.

Results: Differential expression analysis identified 232 proteins in males and 172 in females. STRING analysis revealed sex-specific regulation of proteins. In males, proteins linked to neurofilament organization, myelin integrity, and postsynaptic structure were downregulated, with parvalbumin (Pvalb, PV) around the central node. In contrast, proteins related to mitochondrial and stress-response pathways were upregulated. Female Negr1−/− hippocampus showed downregulation of proteins involved in translation and amide biosynthetic processes. Colocalization of NEGR1 with PV interneurons in the rat brain and the human hippocampus was observed.

Conclusions: We demonstrate, for the first time, distinct sex differences in the hippocampal proteome and identify molecular networks in Negr1−/− mice. Co-localization of NEGR1 and PV in human brain tissue provides anatomical and translational validation of a proteomic target. These findings provide new insight, offering a valuable resource for understanding NEGR1-related sex-specific mechanisms in neuropsychiatric disorders.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13293-026-00890-0.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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The datasets generated and/or analyzed during the current study are available from the corresponding authors on request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 9 keywords, 11 MeSH terms, 1 funder, 72 references.

Cite

This paper

Muthuraman, S., Jayaram, M., Promet, L., Jagomäe, T., Devarajan, A. K., Hade, A.-C., Philips, M.-A., Singh, K., & Vasar, E. (2026). Sex-specific changes in the hippocampal proteome of Negr1<sup>-/-</sup> mice: insight into the mechanisms of neuropsychiatric disorders. Biology of sex differences, 17(1), 96. https://doi.org/10.1186/s13293-026-00890-0

BibTeX

@article{muthuraman2026sex,
author = {Muthuraman, Srirathi and Jayaram, Mohan and Promet, Liisi and Jagomäe, Toomas and Devarajan, Arun Kumar and Hade, Andreas-Christian and Philips, Mari-Anne and Singh, Katyayani and Vasar, Eero},
title = {{Sex-specific changes in the hippocampal proteome of Negr1\<sup\>-/-\</sup\> mice: insight into the mechanisms of neuropsychiatric disorders}},
journal = {Biology of sex differences},
year = {2026},
month = mar,
volume = {17},
number = {1},
pages = {96},
publisher = {BMC},
issn = {2042-6410},
doi = {10.1186/s13293-026-00890-0},
url = {https://doi.org/10.1186/s13293-026-00890-0},
pmid = {41888955},
pmcid = {PMC13141394}
}

RIS

TY - JOUR
AU - Muthuraman, Srirathi
AU - Jayaram, Mohan
AU - Promet, Liisi
AU - Jagomäe, Toomas
AU - Devarajan, Arun Kumar
AU - Hade, Andreas-Christian
AU - Philips, Mari-Anne
AU - Singh, Katyayani
AU - Vasar, Eero
TI - Sex-specific changes in the hippocampal proteome of Negr1<sup>-/-</sup> mice: insight into the mechanisms of neuropsychiatric disorders
T2 - Biology of sex differences
J2 - Biol Sex Differ
PY - 2026
DA - 2026/03/26
VL - 17
IS - 1
SP - 96
SN - 2042-6410
PB - BMC
DO - 10.1186/s13293-026-00890-0
UR - https://doi.org/10.1186/s13293-026-00890-0
LA - en
ER -

CSL-JSON

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