Selective targeting of M‐type potassium Kv7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression‐like behaviour
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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 K v 7.4 channels in modulating excitability of VTA dopaminergic neurons and in the development of depressive behaviour in mice. Experimental Approach: We used K v 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. Key Results: Among the K v 7 channels, K v 7.4 channels are selectively expressed in dopaminergic neurons of the VTA. Using a newly identified selective K v 7.4 channel activator, fasudil, and K v 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 K v 7.4 channels could be a causal factor of the altered excitability of VTA dopaminergic neurons and depression‐like behaviour. The selective K v 7.4 channel activator, fasudil, strongly alleviated depression‐like behaviour in the social defeat mouse model of depression. Conclusion and Implications: Because expression of K v 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, K v 7.4 channels may offer alternative targets in treatment of depression.
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Chronic physical or psychosocial stressors increase ventral tegmental area dopamine neuron activity to elicit depression-like behavior.
“Chronic physical or psychosocial stressors increase VTA dopamine neuron activity to elicit depression-like behavior.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [27]
Following chronic social defeat stress, stress-susceptible animals have increased ventral tegmental area dopamine neuron firing that persists for several weeks after stress termination.
“Following CSDS, stress-susceptible animals have increased VTA dopamine neuron firing [13, 23–29] that persists for several weeks after stress termination [28].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [27]
KCNQ channel Kv7.4 is more selectively expressed in ventral tegmental area (not substantia nigra) dopamine neurons and Kv7.4 currents are reduced in susceptible mice.
“KCNQ channel Kv7.4 is an attractive target in depression, as this subtype is more selectively expressed in VTA (not substantia nigra) dopamine neurons and Kv7.4 currents are reduced in susceptible mice [27].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [27]
KCNQ overexpression or administration of KCNQ-openers rescues depressive behavior by reducing firing of nucleus accumbens projecting, but not prefrontal cortex projecting, ventral tegmental area dopamine neurons.
“KCNQ overexpression or administration of KCNQ-openers rescues depressive behavior [25, 27] by reducing firing of NAc projecting, but not PFC projecting VTA dopamine neurons [25].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [27]
Sucrose preference deficits, social avoidance, and ventral tegmental area excitability are reduced by opening Kv7.4 channels with fasudil.
“Sucrose preference deficits, social avoidance, and VTA excitability are reduced by opening Kv7.4 channels with fasudil [27]”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [27]
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- Authors
- Li, L., Sun, H., Ding, J., Niu, C., Su, M., Zhang, L., Li, Y., Wang, C., Gamper, N., Du, X., & Zhang, H.
- Affiliations
- Hebei Medical University (CN)
- Corresponding author
- Zhang, Hailin
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2017-10-19
- Volume
- 174
- Issue
- 23
- Pages
- 4277-4294
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC5715975
- OpenAlex
- W2797640728
- Cited by
- 51
- References
- 53
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 11 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 1
- FWCI
- 1.23
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Funders
- Ministry of Science and Technology of the People's Republic of China (2013CB531302)
- National Natural Science Foundation of China (31270882)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- M-type potassium channels, ventral tegmental area, dopaminergic neurons, neuronal excitability, depression-like behavior, social defeat, fasudil, mesolimbic dopamine system
- MeSH terms
- Animals, Behavior, Animal, Depression, Disease Models, Animal, Male, Mice, Inbred C57BL, Social Behavior, Ventral Tegmental Area, Mice, Knockout, Patch-Clamp Techniques, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Mice, KCNQ Potassium Channels, Dopaminergic Neurons
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