Chronic social defeat stress induces the down-regulation of the Nedd4L-GLT-1 ubiquitination pathway in the prefrontal cortex of mice.

Autor: Kosuge A; Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan., Kunisawa K; Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan., Iida T; Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan., Wulaer B; Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Science, Toyoake, Aichi, Japan.; Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan., Kawai T; Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan., Tanabe M; Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan., Saito K; Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Science, Toyoake, Aichi, Japan.; Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan.; Laboratory of Health and Medical Science Innovation, Fujita Health University Graduate School of Health Science, Toyoake, Aichi, Japan.; Japanese Drug Organization of Appropriate Use and Research, Toyoake, Aichi, Japan., Nabeshima T; Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Science, Toyoake, Aichi, Japan.; Laboratory of Health and Medical Science Innovation, Fujita Health University Graduate School of Health Science, Toyoake, Aichi, Japan.; Japanese Drug Organization of Appropriate Use and Research, Toyoake, Aichi, Japan., Mouri A; Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan.; Japanese Drug Organization of Appropriate Use and Research, Toyoake, Aichi, Japan.
Jazyk: angličtina
Zdroj: Journal of neurochemistry [J Neurochem] 2024 Sep; Vol. 168 (9), pp. 2479-2494. Date of Electronic Publication: 2024 Mar 18.
DOI: 10.1111/jnc.16100
Abstrakt: Stressful life events contribute to the onset of major depressive disorder (MDD). We recently demonstrated abnormalities in ubiquitination in the pathophysiology of MDD. However, the underlying molecular mechanisms remain unclear. We investigated the involvement of the ubiquitination system-mediated glutamatergic dysfunction in social impairment induced by chronic social defeat stress (CSDS). Adult C57BL/6J mice were exposed to aggressor ICR male mice for 10 consecutive days. Social impairment was induced by CSDS in the social interaction test 1 days after the last stress exposure. In terms of brain microdialysis, CSDS reduced depolarization-evoked glutamate release in the prefrontal cortex (PFC), which was reversed by a glutamate transporter 1 (GLT-1) inhibitor. Interestingly, the expression of ubiquitinated, but not total GLT-1, was decreased in the PFC of mice exposed to CSDS. The expression of neural precursor cells expressing developmentally downregulated gene 4-like (Nedd4L: E3 ligase for GLT-1), and ubiquitin-conjugating enzyme E2D2 (Ube2d2: E2 ubiquitin-conjugating enzyme for Nedd4L) was also reduced in CSDS mice. Furthermore, the downregulation of the Nedd4L-GLT-1 ubiquitination pathway decreased SIT ratio, but up-regulation increased it even in non-CSDS mice. Taken together, the decrease in GLT-1 ubiquitination may reduce the release of extracellular glutamate induced by high-potassium stimulation, which may lead to social impairment, while we could not find differences in GLT-1 ubiquitination between susceptible and resistant CSDS mice. In conclusion, GLT-1 ubiquitination could play a crucial role in the pathophysiology of MDD and is an attractive target for the development of novel antidepressants.
(© 2024 International Society for Neurochemistry.)
Databáze: MEDLINE
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