Selective targeting of M‐type potassium K_v7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression‐like behaviour

Abstract

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 APPROACHWe 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.

Kv7.4 Channel Contribute to Projection-Specific Auto-Inhibition of Dopamine Neurons in the Ventral Tegmental Area

“…Earlier findings by us (Li et al, 2017) and others (Hansen et al, 2006) demonstrated that the Kv7.4 subunit of Kv7 is selectively expressed in the midbrain, especially in the VTA (Li et al, 2017). The aim of this study was 3-fold: (i) to determine the projection-specific expression pattern of Kv7.4 in VTA DA neurons; (ii) to identify Kv7.4 as a target of D2 receptor-mediated auto-inhibition of VTA DA neurons; and (iii) to probe the involvement of D2-Kv7.4 pathway mechanism in a social defeat mouse model of depression.…”

“…The details of coronal VTA brain slice preparation were the same as our previously published work (Li et al, 2017). Recordings in the slices were performed in whole-cell current-clamp and voltage-clamp configurations on an Axopatch 1D amplifier coupled with a Digidata 1440A AD converter (Molecular Devices, San Jose, CA, USA).…”

“…Processes of immunohistochemistry were performed as previously described (Li et al, 2017), with some modifications. The DAPI-stained coronal midbrain sections (200 µm-thick) from mice that were injected with retrobeads were reconstructed with CaseViewer (Pannoramic MIDI, 3DHISTECH, Hungary).…”

“…Complete experimental methods for chronic social defeat model were described in our previously published work (Li et al, 2017).…”

“…Another K + channel family that appears to be an important regulator of VTA DA firing/activity is the Kv7/KCNQ channels (Jentsch, 2000;Li et al, 2017). Four members of Kv7/KCNQ channels (Kv7.2-7.5) are expressed in the CNS (Jentsch, 2000).…”