Kv7.2 subunit-containing M-type potassium channels in the lateral habenula are involved in the regulation of working memory in parkinsonian rats

Guanyun Bian; Jian Liu; Yuan Guo; Yaxin Yang; Libo Li; Hongfei Qiao; Wenjuan Li; Tian Xu; Qiaojun Zhang

doi:10.1016/j.neuropharm.2020.108012

Kv7.2 subunit-containing M-type potassium channels in the lateral habenula are involved in the regulation of working memory in parkinsonian rats

Neuropharmacology. 2020 May 15:168:108012. doi: 10.1016/j.neuropharm.2020.108012. Epub 2020 Feb 15.

Authors

Guanyun Bian¹, Jian Liu², Yuan Guo², Yaxin Yang¹, Libo Li¹, Hongfei Qiao¹, Wenjuan Li¹, Tian Xu¹, Qiaojun Zhang³

Affiliations

¹ Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
² Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
³ Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China. Electronic address: zhangqj@mail.xjtu.edu.cn.

PMID: 32067988
DOI: 10.1016/j.neuropharm.2020.108012

Abstract

Although the lateral habenula (LHb) is involved in the regulation of multiple brain functions and this region expresses abundant M-type potassium channel (M-channel) subunits Kv7.2 and Kv7.3, the role of M-channels in regulating working memory is unclear, particularly in Parkinson's disease (PD). Here we tested the effects of activation and blockade of LHb M-channels on working memory by the T-maze rewarded alternation test in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc). The SNc lesion induced working memory impairment, increased the firing rate of LHb neurons, decreased dopamine (DA) level in the ventral medial prefrontal cortex (vmPFC) and reduced the expression of Kv7.2 subunit in the LHb. Intra-LHb injection of M-channel activator retigabine induced enhancement of working memory in SNc sham-lesioned and SNc-lesioned rats; conversely, the injection of M-channel blocker XE-991 impaired working memory in the two groups of rats. However, doses producing significant effects in SNc-lesioned rats were higher than those in SNc sham-lesioned rats. Further, intra-LHb injection of retigabine decreased the firing rate of LHb neurons and increased release of DA and serotonin (5-HT) in the vmPFC, while XE-991 increased the firing rate and decreased DA and 5-HT release in the two groups of rats. Compared with SNc sham-lesioned rats, the duration of M-channel activation and blockade action on the firing rate of the neurons and release of DA and 5-HT was significantly shortened in SNc-lesioned rats, which was consistent with reduced expression of Kv7.2 subunit in the LHb after lesioning the SNc. Collectively, these findings suggest involvement of LHb Kv7.2 subunit-containing M-channels in working memory impairment in SNc-lesioned rats, and that enhanced or impaired working memory after activation or blockade of M-channels in the LHb is related to the changes in the firing activity of LHb neurons and DA and 5-HT release in the vmPFC.

Keywords: Lateral habenula; M-type potassium channels; Parkinson's disease; Rat; Working memory.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Habenula / drug effects
Habenula / metabolism*
KCNQ2 Potassium Channel / agonists
KCNQ2 Potassium Channel / antagonists & inhibitors
KCNQ2 Potassium Channel / biosynthesis*
Male
Membrane Transport Modulators / pharmacology
Memory, Short-Term / drug effects
Memory, Short-Term / physiology*
Oxidopamine / toxicity
Parkinsonian Disorders / chemically induced
Parkinsonian Disorders / metabolism*
Potassium Channel Blockers / pharmacology
Protein Subunits / biosynthesis
Rats
Rats, Sprague-Dawley

Substances

KCNQ2 Potassium Channel
Membrane Transport Modulators
Potassium Channel Blockers
Protein Subunits
Oxidopamine