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HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization

Mood instability, a subjective emotional state defined as rapid mood oscillations of up and down, is a symptom that occurs in several psychiatric disorders, particularly major depressive disorder and bipolar disorder. Heat shock protein A12A (HSPA12A) shows decreased expression in the brains of schi...

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Autores principales: Wang, Jialing, Lu, Ting, Gui, Yali, Zhang, Xiaojin, Cao, Xiaofei, Li, Yuehua, Li, Chuanfu, Liu, Li, Ding, Zhengnian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425330/
https://www.ncbi.nlm.nih.gov/pubmed/37580315
http://dx.doi.org/10.1038/s41398-023-02573-5
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author Wang, Jialing
Lu, Ting
Gui, Yali
Zhang, Xiaojin
Cao, Xiaofei
Li, Yuehua
Li, Chuanfu
Liu, Li
Ding, Zhengnian
author_facet Wang, Jialing
Lu, Ting
Gui, Yali
Zhang, Xiaojin
Cao, Xiaofei
Li, Yuehua
Li, Chuanfu
Liu, Li
Ding, Zhengnian
author_sort Wang, Jialing
collection PubMed
description Mood instability, a subjective emotional state defined as rapid mood oscillations of up and down, is a symptom that occurs in several psychiatric disorders, particularly major depressive disorder and bipolar disorder. Heat shock protein A12A (HSPA12A) shows decreased expression in the brains of schizophrenia patients. However, the causal effects of HSPA12A in any psychiatric disorders are completely unknown. To investigate whether HSPA12A affects mood stability, Hspa12a-knockout mice (Hspa12a(−)(/−)) and wild-type (WT) littermates were subjected to tests of open field, forced swimming, elevated plus maze, and sucrose preference. Cerebral lactate levels were measured in cerebrospinal fluid (CSF). Adult hippocampal neurogenesis (AHN) was assessed by BrdU labeling. We found that acute mood stress increased hippocampal HSPA12A expression and CSF lactate levels in mice. However, Hspa12a(−)(/−) mice exhibited behaviors of mood instability (anhedonia, lower locomotor activity, antidepression, and anxiety), which were accompanied by impaired AHN, decreased CSF lactate levels, and downregulated hippocampal glycolytic enzyme expression. By contrast, HSPA12A overexpression increased lactate production and glycolytic enzyme expression of primary hippocampal neurons. Intriguingly, lactate administration alleviated the mood instability and AHN impairment in Hspa12a(−)(/−) mice. Further analyses revealed that HSPA12A was necessary for sustaining cerebral lactate homeostasis, which could be mediated by inhibiting GSK3β in hippocampal neurons, to maintain AHN and mood stabilization. Taken together, HSPA12A is defined as a novel regulator of mood stability and exerts therapeutic potential for mood disorder. Our findings establish a framework for determining mood disorder and AHN relevance of cerebral lactate homeostasis. [Figure: see text]
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spelling pubmed-104253302023-08-16 HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization Wang, Jialing Lu, Ting Gui, Yali Zhang, Xiaojin Cao, Xiaofei Li, Yuehua Li, Chuanfu Liu, Li Ding, Zhengnian Transl Psychiatry Article Mood instability, a subjective emotional state defined as rapid mood oscillations of up and down, is a symptom that occurs in several psychiatric disorders, particularly major depressive disorder and bipolar disorder. Heat shock protein A12A (HSPA12A) shows decreased expression in the brains of schizophrenia patients. However, the causal effects of HSPA12A in any psychiatric disorders are completely unknown. To investigate whether HSPA12A affects mood stability, Hspa12a-knockout mice (Hspa12a(−)(/−)) and wild-type (WT) littermates were subjected to tests of open field, forced swimming, elevated plus maze, and sucrose preference. Cerebral lactate levels were measured in cerebrospinal fluid (CSF). Adult hippocampal neurogenesis (AHN) was assessed by BrdU labeling. We found that acute mood stress increased hippocampal HSPA12A expression and CSF lactate levels in mice. However, Hspa12a(−)(/−) mice exhibited behaviors of mood instability (anhedonia, lower locomotor activity, antidepression, and anxiety), which were accompanied by impaired AHN, decreased CSF lactate levels, and downregulated hippocampal glycolytic enzyme expression. By contrast, HSPA12A overexpression increased lactate production and glycolytic enzyme expression of primary hippocampal neurons. Intriguingly, lactate administration alleviated the mood instability and AHN impairment in Hspa12a(−)(/−) mice. Further analyses revealed that HSPA12A was necessary for sustaining cerebral lactate homeostasis, which could be mediated by inhibiting GSK3β in hippocampal neurons, to maintain AHN and mood stabilization. Taken together, HSPA12A is defined as a novel regulator of mood stability and exerts therapeutic potential for mood disorder. Our findings establish a framework for determining mood disorder and AHN relevance of cerebral lactate homeostasis. [Figure: see text] Nature Publishing Group UK 2023-08-14 /pmc/articles/PMC10425330/ /pubmed/37580315 http://dx.doi.org/10.1038/s41398-023-02573-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Jialing
Lu, Ting
Gui, Yali
Zhang, Xiaojin
Cao, Xiaofei
Li, Yuehua
Li, Chuanfu
Liu, Li
Ding, Zhengnian
HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization
title HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization
title_full HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization
title_fullStr HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization
title_full_unstemmed HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization
title_short HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization
title_sort hspa12a controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425330/
https://www.ncbi.nlm.nih.gov/pubmed/37580315
http://dx.doi.org/10.1038/s41398-023-02573-5
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