L-DOPA reverses the impaired working memory via lateral habenula Kv7.2 subunit-containing M-channels in experimental parkinsonism

Guanyun Bian; Jian Liu; Yanping Hui; Libo Li; Yaxin Yang; Qiaojun Zhang

doi:10.1016/j.pbb.2025.174062

L-DOPA reverses the impaired working memory via lateral habenula Kv7.2 subunit-containing M-channels in experimental parkinsonism

Pharmacol Biochem Behav. 2025 Jul 11:174062. doi: 10.1016/j.pbb.2025.174062. Online ahead of print.

Authors

Guanyun Bian¹, Jian Liu², Yanping Hui¹, Libo Li¹, Yaxin Yang¹, 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: 40652990
DOI: 10.1016/j.pbb.2025.174062

Abstract

Non-motor symptoms such as cognitive deficits are often observed in Parkinson's disease, and the effect of L-3,4-dihydroxyphenylalanin (L-DOPA) treatment on working memory in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc) and underlying mechanisms are unclear. In adult male Sprague-Dawley rats, we found that L-DOPA treatment in SNc-lesioned rats reversed working memory impairment, decreased the firing rate of the lateral habenula (LHb) neurons, increased dopamine (DA) levels in the medial prefrontal cortex (mPFC) and hippocampus, and reversed reduced expression of M-channel Kv7.2 subunit in the LHb compared with SNc-lesioned rats treated with normal saline (NS). Intra-LHb injection of M-channel activator retigabine or blocker XE-991 induced enhancement or impairment of working memory in SNc-lesioned rats treated with L-DOPA, along with alterations of DA levels in the mPFC and hippocampus. However, the same doses of the two drugs produced no significant effects on working memory and DA levels in SNc-lesioned rats treated with NS. Further, M-channel activate or blockade decreased or increased the firing rate of LHb neurons, and the duration of M-channel stimulation on the firing rate of the neurons in SNc-lesioned rats treated L-DOPA was longer than those in SNc-lesioned rats treated with NS, which was consistent with up-regulation of Kv7.2 subunit in the LHb. Collectively, these findings suggest that L-DOPA treatment up-regulates the expression of M-channel Kv7.2 subunit in the LHb, and then induces decreased activity of LHb neurons and increased DA levels in the mPFC and hippocampus, which reverse working memory impairment in parkinsonian rats.

Keywords: Kv7.2 subunit-containing M-channels; L-DOPA; Lateral habenula; Parkinson's disease; Working memory.