GABA(B) receptor activation contributes to post-surgery cognitive impairments in mice by inducing hippocampal BDNF hypermethylation.

BACKGROUND: Clinical observations have shown that brain-derived neurotrophic factor (BDNF) expression is reduced in patients with impaired cognitive function after anaesthesia and surgery. Abnormal epigenetic changes may contribute to this condition. The role of the GABAergic system, which is crucial in anaesthetic mechanisms and cognitive function, requires further investigation to determine whether it affects BDNF epigenetic regulation and cognitive outcomes. MATERIALS AND METHODS: Experiments employed a mouse model perioperative neurocognitive disorder (PND) that comprised laparotomy under isoflurane inhalation anaesthesia. Mice were subjected to behavioural assessments, including the Y-maze and novel object recognition tests for cognitive function and molecular analyses (quantitative polymerase chain reaction, qPCR) and methylation-specific PCR to assess BDNF expression and epigenetic modifications. GABA(B) receptor deactivation was induced by a selective antagonist and changes in BDNF expression and gene methylation were measured. RESULTS: Aged mice in the PND model had reduced BDNF expression in hippocampal neurons. BDNF protein reduction was linked to increased methylation of the Bdnf gene, initiated by GABA(B) receptor activation and hyperphosphorylation of downstream signalling proteins. Furthermore, BDNF overexpression experiments demonstrated a partial reversal of cognitive impairment in mice, supporting a causal role for BDNF methylation in PND. CONCLUSIONS: This study emphasizes the vital interaction between the GABAergic system and the epigenetic control of Bdnf, shedding light on the mechanisms underlying anaesthesia-related cognitive impairment. Our findings suggest that inhibition of GABA(B) receptor activation to reverse BDNF hypermethylation may represent a potential therapeutic strategy for alleviating PND.