Chronic Treatment with Anti-bipolar Drugs Down-Regulates Gene Expression of TRPC1 in Neurones.

Ting Du,Alexei Verkhratsky,Rui Feng,Liang Peng,Yan Rong

doi:10.3389/fncel.2016.00305

Abstract

In the brain, TRPC1 channels are abundantly expressed in neurones virtually in all regions; these proteins function as receptor-activated ion channels and are implicated in numerous processes, being specifically important for neurogenesis. Primary cultures of mouse cerebellar granule cell, cerebral cortical neurones, and freshly isolated neurones from in vivo brains were used to study effects of chronic treatment with anti-bipolar drugs [carbamazepine (CBZ), lithium salts and valproic acid] on gene expression of TRPC1. Expression of TRPC1 mRNA was identified with reverse transcription-polymerase chain reaction, whereas protein content was determined by Western blotting. Store-operated plasmalemmal Ca2+ entry (SOCE) was measured with fura-2 based microfluorimetry. Chronic treatment with each of the three drugs down-regulated mRNA and protein expression in cultured cerebellar granule cells in a time- and concentration-dependent manner. Similar effect was also observed in cultured cerebral cortical neurones treated with CBZ, lithium salts and valproic acid and in freshly isolated neurones from the brains of CBZ-treated animals. The amplitude of SOCE was substantially decreased in cerebellar granule cells chronically treated with each of the three drugs. Our findings indicate that down-regulation of TRPC1 gene expression and function in neurones may be one of the mechanisms of anti-bipolar drugs action.

Highlights

Bipolar disorder (BD) is a common, devastating and chronic mental disease that affects 1–3% of the population (Goodwin and Jamison, 2007)
In olfactory bulb granule cells transient receptor potential channel 1 (TRPC1), as well as TRPC4, can be activated downstream of NMDA receptors and contribute to slow dendritic GABA release (Stroh et al, 2012). These findings suggest that TRPC1 contributes to multiple signals instigated by activation of glutamate receptors, and a decrease of TRPC1 expression and function by anti-bipolar drugs may overcome of the abnormal overactivity of glutamate receptors that develops in BD
For the first time, that gene expression of neuronal TRPC1 is decreased by all three anti-bipolar drugs

Summary

Introduction

Bipolar disorder (BD) is a common, devastating and chronic mental disease that affects 1–3% of the population (Goodwin and Jamison, 2007). Given CBZ, Li+, and VPA share no similarity in chemical structures, revealing downstream effects of all three drugs is important for further understanding drug targets and the pathophysiology of the disease. We have found several genes that are regulated by chronic treatment with anti-bipolar drugs in astrocytes (for review, see Peng et al, 2016). These includes down-regulation of gene expression of glutamate kainate receptor GluK2 (Li et al, 2009), the Ca2+-dependent phospholipase A2 (Li et al, 2007) and transient receptor potential channel 1 (TRPC1); a cation channel, which in astroglia is activated by ER store depletion and contributes to the store-operated Ca2+ entry, SOCE (Yan et al, 2013)

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Conclusion