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Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour.

Authors :
Li, Li
Sun, Hui
Ding, Jie
Niu, Chenxu
Su, Min
Zhang, Ludi
Li, Yingmin
Wang, Chuan
Gamper, Nikita
Du, Xiaona
Zhang, Hailin
Source :
British Journal of Pharmacology; Dec2017, Vol. 174 Issue 23, p4277-4294, 18p, 6 Graphs
Publication Year :
2017

Abstract

<bold>Background and Purpose: </bold>The mesolimbic dopamine system originating in the ventral tegmental area (VTA) is involved in the development of depression, and firing patterns of VTA dopaminergic neurons are key determinants in this process. Here, we describe a crucial role for the M-type Kv 7.4 channels in modulating excitability of VTA dopaminergic neurons and in the development of depressive behaviour in mice.<bold>Experimental Approach: </bold>We used Kv 7.4 channel knockout mice and a social defeat model of depression in combination with electrophysiological techniques (patch clamp recording and in vivo single-unit recordings), immunohistochemistry, single-cell PCR and behavioural analyses (social interaction time and glucose preference tests) to investigate VTA circuits involved in the development of depression-like behaviour.<bold>Key Results: </bold>Among the Kv 7 channels, Kv 7.4 channels are selectively expressed in dopaminergic neurons of the VTA. Using a newly identified selective Kv 7.4 channel activator, fasudil, and Kv 7.4 channel knockout mice, we demonstrate that these channels are a dominant modulator of excitability of VTA dopaminergic neurons, in vitro and in vivo. Down-regulation of Kv 7.4 channels could be a causal factor of the altered excitability of VTA dopaminergic neurons and depression-like behaviour. The selective Kv 7.4 channel activator, fasudil, strongly alleviated depression-like behaviour in the social defeat mouse model of depression.<bold>Conclusion and Implications: </bold>Because expression of Kv 7.4 channels in the CNS is limited, selectively targeting this M channel subunit is likely to produce less on-target side effects than non-selective M channel modulators. Thus, Kv 7.4 channels may offer alternative targets in treatment of depression. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00071188
Volume :
174
Issue :
23
Database :
Complementary Index
Journal :
British Journal of Pharmacology
Publication Type :
Academic Journal
Accession number :
126564482
Full Text :
https://doi.org/10.1111/bph.14026