期刊
SCIENTIFIC REPORTS
卷 10, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-020-61248-z
关键词
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资金
- Canadian Institutes of Health Research [MOP-136916]
- Instituto Nacional de Ciencia e Tecnologia de Medicina Molecular [FAPEMIG CBB-APQ-00075-09, CNPq 573646/2008-2]
- Fundacao de Amparo a Pesquisa do Estado de Minas Gerais [APQ 00476-14]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [457639/2014-8]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior Brasil [001, 88887.364938/2019-00]
Peripheral biomarker and post-mortem brains studies have shown alterations of neuronal calcium sensor 1 (Ncs-1) expression in people with bipolar disorder or schizophrenia. However, its engagement by psychiatric medications and potential contribution to behavioral regulation remains elusive. We investigated the effect on Ncs-1 expression of valproic acid (VPA), a mood stabilizer used for the management of bipolar disorder. Treatment with VPA induced Ncs-1 gene expression in cell line while chronic administration of this drug to mice increased both Ncs-1 protein and mRNA levels in the mouse frontal cortex. Inhibition of histone deacetylases (HDACs), a known biochemical effect of VPA, did not alter the expression of Ncs-1. In contrast, pharmacological inhibition or genetic downregulation of glycogen synthase kinase 3 beta (Gsk3 beta) increased Ncs-1 expression, whereas overexpression of a constitutively active Gsk3 beta had the opposite effect. Moreover, adeno-associated virus-mediated Ncs-1 overexpression in mouse frontal cortex caused responses similar to those elicited by VPA or lithium in tests evaluating social and mood-related behaviors. These findings indicate that VPA increases frontal cortex Ncs-1 gene expression as a result of Gsk3 inhibition. Furthermore, behavioral changes induced by Ncs-1 overexpression support a contribution of this mechanism in the regulation of behavior by VPA and potentially other psychoactive medications inhibiting Gsk3 activity.
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