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

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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