CDK5-Induced HCN2 Channel Dysfunction in the Prelimbic Cortex Drives Allodynia and Anxiety-Like Behaviors in Neuropathic Pain.
10.1007/s12264-025-01546-6
- Author:
Lu CHEN
1
;
Shuai CAO
1
;
Yun-Ze LIU
1
;
Qi-Fan YANG
1
;
Jin-Yu YANG
1
;
Dan-Yang ZHANG
1
;
Guo-Guang XIE
1
;
Xiang-Sha YIN
1
;
Ying ZHANG
2
;
Yun WANG
3
Author Information
1. Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education, National Health Commission and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.
2. Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education, National Health Commission and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China. zhangyingnri@bjmu.edu.cn.
3. Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education, National Health Commission and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China. wangy66@bjmu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Chronic pain;
Hyperpolarization-activated cation current;
Phosphorylation;
Prefrontal cortex;
Spared nerve injury
- MeSH:
Animals;
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism*;
Hyperalgesia/metabolism*;
Cyclin-Dependent Kinase 5/metabolism*;
Neuralgia/metabolism*;
Male;
Anxiety/metabolism*;
Mice;
Potassium Channels/metabolism*;
Mice, Inbred C57BL;
Disease Models, Animal;
Pyramidal Cells/metabolism*
- From:
Neuroscience Bulletin
2025;41(12):2254-2271
- CountryChina
- Language:English
-
Abstract:
The prelimbic cortex (PL) plays a critical role in processing both the sensory and affective components of pain. However, the underlying molecular mechanisms remain poorly understood. In this study, we observed a reduction in hyperpolarization-activated cation current (Ih) in layer V pyramidal neurons of the contralateral PL in a mouse model of spared nerve injury (SNI). The expression of hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channels was also decreased in the contralateral PL. Conversely, microinjection of fisetin, a partial agonist of HCN2, produced both analgesic and anxiolytic effects. Additionally, we found that cyclin-dependent kinase 5 (CDK5) was activated in the contralateral PL, where it formed a complex with HCN2 and phosphorylated its C-terminus. Knockdown of CDK5 restored HCN2 expression and alleviated both pain hypersensitivity and anxiety-like behaviors. Collectively, these results indicate that CDK5-mediated dysfunction of HCN2 in the PL underlies nerve injury-induced mechanical hypersensitivity and anxiety.
