Selective targeting of M-type potassium channel Kv7.4 demonstrates its key role in regulating of dopaminergic neuronal excitability and depression-like behaviour

Background and Purpose The mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) is implicated in the development of depression, and firing patterns of VTA DA neurons are key determinants in this process. Here, we describe a crucial role of the M-type potassium channel Kv7.4 in modulation of VTA DA neuronal excitability and in the development of depressive behaviour in mice. Experimental Approach We used Kv7.4 knock-out mice and a social defeat model of depression in combination with various 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 development of depression-like behaviour. Key results We demonstrate that among the Kv7 channel subunits, Kv7.4 is selectively expressed in dopamine neurons of the VTA. Using a newly identified selective Kv7.4 activator fasudil and Kv7.4 knock-out mice, we demonstrate that Kv7.4 is a dominant modulator of VTA DA neuronal excitability in vitro and in vivo. The results also demonstrate that down-regulation of Kv7.4 could be a causal factor of the altered excitability of VTA DA neurons and depression-like behaviour. Finally, the selective Kv7.4 activator fasudil strongly alleviated depression-like behaviour in the social defeat mouse model of depression. Conclusion and Implications Because expression of Kv7.4 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, and thus, Kv7.4 may offer an alternative target for treating depression.