Abstract
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 3β (Gsk3β) increased Ncs-1 expression, whereas overexpression of a constitutively active Gsk3β 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.
Highlights
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
We found a significant upregulation of both Ncs-1 protein (96%) and mRNA (1.6-fold increase) that were restricted to the frontal cortex of mice chronically treated with valproic acid (VPA) (VPA vs. vehicle: mean difference (MD) = 0.96, 95% CI [0.14 to 1.78], t(6) = 2.717, p = 0.026; VPA vs. vehicle: MD = 0.59, 95% CI [0.09 to 1.09], t(6) = 2.718, p = 0.026; n = 5/ group, Student’s t-tests; Fig. 1c–f)
We found that chronic treatment with the mood stabilizer VPA upregulates Ncs-1 in cell lines and the mouse frontal cortex (Fig. 1), which is likely to be mediated by inhibition of Gsk[3] (Figs. 2, 3 and S2)
Summary
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. 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 Gsk[3] inhibition. VPA is a first-line treatment for depressive and manic phases of bipolar disorder[12] It alters gene expression and promotes neuroplasticity changes, which in recent years has been suggested to underlie malfunctioning of the neurocircuits related to the psychiatric symptoms[13,14,15]. VPA targets multiple neuronal processes mediated by Gsk[3] and appear to depend on Gsk[3] signaling to achieve behavioral regulation in preclinical animal models[18,19,29,30]
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