Li, L, Sun, H, Ding, J et al. (8 more authors) (2017) Selective targeting of M‐type potassium Kv7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression‐like behaviour. British Journal of Pharmacology, 174 (23). pp. 4277-4294. ISSN 0007-1188
Abstract
Background and Purpose: 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 Kv7.4 channels in modulating excitability of VTA dopaminergic neurons and in the development of depressive behaviour in mice. Experimental Approach: We used Kv7.4 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. Key Results: Among the Kv7 channels, Kv7.4 channels are selectively expressed in dopaminergic neurons of the VTA. Using a newly identified selective Kv7.4 channel activator, fasudil, and Kv7.4 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 Kv7.4 channels could be a causal factor of the altered excitability of VTA dopaminergic neurons and depression‐like behaviour. The selective Kv7.4 channel activator, fasudil, strongly alleviated depression‐like behaviour in the social defeat mouse model of depression. Conclusion and Implications: Because expression of Kv7.4 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, Kv7.4 channels may offer alternative targets in treatment of depression.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 The British Pharmacological Society. This is the peer reviewed version of the following article: Li, L., Sun, H., Ding, J., Niu, C., Su, M., Zhang, L., Li, Y., Wang, C., Gamper, N., Du, X., and Zhang, H. (2017) Selective targeting of M‐type potassium Kv7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression‐like behaviour. British Journal of Pharmacology, 174: 4277–4294. doi: 10.1111/bph.14026., which has been published in final form at https://doi.org/10.1111/bph.14026. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 26 Sep 2017 09:36 |
Last Modified: | 08 Sep 2018 00:38 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1111/bph.14026 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:121651 |