GPER1 deficiency causes sex-specific dysregulation of hippocampal plasticity and cognitive function

in Journal of Endocrinology
Authors:
Aune Koitmäe Institute of Neuroanatomy, University Medical Center Hamburg, Hamburg, Germany

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Yannik Karsten Institute of Neuroanatomy, University Medical Center Hamburg, Hamburg, Germany
Department of Genetics and Molecular Biology, Institute of Biology, University of Magdeburg, Magdeburg, Germany

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Xiaoyu Li Institute of Neuroanatomy, University Medical Center Hamburg, Hamburg, Germany
Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Jiangsu, China

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Fabio Morellini Research Group Behavioral Biology, Center for Molecular Neurobiology, Hamburg, Germany

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Gabriele M Rune Institute of Cell Biology and Neurobiology, Universitätsmedizin Charité Berlin, Berlin, Germany

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Roland A Bender Institute of Neuroanatomy, University Medical Center Hamburg, Hamburg, Germany

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https://orcid.org/0000-0003-1080-1584

Correspondence should be addressed to R A Bender: r.bender@uke.de

*(A Koitmäe and Y Karsten contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-22-0204
Volume/Issue:
Volume 258: Issue 3
Article Type:
Research Article
Article ID:
e220204
Online Publication Date:
02 Aug 2023
Copyright:
© the author(s) 2023
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Estrogens regulate synaptic properties and influence hippocampus-related learning and memory via estrogen receptors, which include the G-protein-coupled estrogen receptor 1 (GPER1). Studying mice, in which the GPER1 gene is dysfunctional (GPER1-KO), we here provide evidence for sex-specific roles of GPER1 in these processes. GPER1-KO males showed reduced anxiety in the elevated plus maze, whereas the fear response ('freezing') was specifically increased in GPER1-KO females in a contextual fear conditioning paradigm. In the Morris water maze, spatial learning and memory consolidation was impaired by GPER1 deficiency in both sexes. Notably, in the females, spatial learning deficits and the fear response were more pronounced if mice were in a stage of the estrous cycle, in which E2 serum levels are high (proestrus) or rising (diestrus). On the physiological level, excitability at Schaffer collateral synapses in CA1 increased in GPER1-deficient males and in proestrus/diestrus ('E2 high') females, concordant with an increased hippocampal expression of the AMPA-receptor subunit GluA1 in GPER1-KO males and females as compared to wildtype males. Further changes included an augmented early long-term potentiation (E-LTP) maintenance specifically in GPER1-KO females and an increased hippocampal expression of spinophilin in metestrus/estrus ('E2 low') GPER1-KO females. Our findings suggest modulatory and sex-specific functions of GPER1 in the hippocampal network, which reduce rather than increase neuronal excitability. Dysregulation of these functions may underlie sex-specific cognitive deficits or mood disorders.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© the author(s) 2023
Article ID:
e220204
Article Type:
Research Article
Received Date:
25 Aug 2022
Accepted Date:
03 Jul 2023
Print Publication Date:
01 Sep 2023
Online Publication Date:
02 Aug 2023
Keywords:
steroid hormone; hippocampus; spatial learning; fear conditioning; LTP; AMPA receptor

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