HDAC2 modulation of KCC2 in the anterior cingulate cortex impairs synaptic plasticity in chronic neuropathic pain with cognitive impairment

This study explores the role of histone deacetylase 2 (HDAC2) in the anterior cingulate cortex (ACC) in chronic pain-related cognitive impairment following chronic constriction injury (CCI). Behavioral tests, molecular analyses, and neuronal morphology assessments revealed that HDAC2 expression was markedly increased in the ACC of CCI mice, accompanied by reduced dendritic spine density and cognitive deficits. Pharmacological inhibition or small interfering RNA (siRNA)-mediated knockdown of HDAC2 alleviated pain hypersensitivity and improved cognition, whereas adeno-associated virus (AAV)-mediated HDAC2 overexpression induced similar pathological features in naive mice. Moreover, HDAC2 upregulation suppressed potassium-chloride cotransporter 2 (KCC2) expression, suggesting that HDAC2 modulates synaptic plasticity through epigenetic repression of KCC2. Restoration of KCC2 expression or inhibition of HDAC2 rescued dendritic abnormalities and behavioral impairments. Restoration of KCC2 activity via the specific agonist CLP257 rescued dendritic spine abnormalities, normalized ACC neuronal hyperexcitability, and alleviated both pain and cognitive impairment in CCI mice. These findings indicate that HDAC2 contributes to neuropathic pain-related cognitive dysfunction by epigenetically suppressing KCC2, which in turn impairs synaptic plasticity and disrupts neuronal excitability in the ACC.