CDK5-Induced HCN2 Channel Dysfunction in the Prelimbic Cortex Drives Allodynia and Anxiety-Like Behaviors in Neuropathic Pain
Lu Chen1 · Shuai Cao1 · Yun‑Ze Liu1 · Qi‑Fan Yang1 · Jin‑Yu Yang1 · Dan‑Yang Zhang1 · Guo‑Guang Xie1 · Xiang‑Sha Yin1 · Ying Zhang1 · Yun Wang1,2
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 PKU‑IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
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.
Keywords
Chronic pain · Prefrontal cortex · Hyperpolarization-activated cation current · Spared nerve injury · Phosphorylation
