Reduced brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA) neurotransmission co-occur in brain conditions (depression, schizophrenia and age-related disorders) and are associated with symptomatology. Rodent studies show they are causally linked, suggesting the presence of biological pathways mediating this link. Here we first show that reduced BDNF and GABA also co-occur with attenuated autophagy in human depression. Using mice, we then show that reducing Bdnf levels (Bdnf^+/−) leads to upregulated sequestosome-1/p62, a key autophagy-associated adaptor protein, whose levels are inversely correlated with autophagic activity. Reduced Bdnf levels also caused reduced surface presentation of α5 subunit-containing GABA_A receptor (α5-GABA_AR) in prefrontal cortex (PFC) pyramidal neurons. Reducing p62 gene dosage restored α5-GABA_AR surface expression and rescued PFC-relevant behavioral deficits of Bdnf^+/− mice, including cognitive inflexibility and reduced sensorimotor gating. Increasing p62 levels was sufficient to recreate the molecular and behavioral profiles of Bdnf^+/− mice. Collectively, the data reveal a novel mechanism by which deficient BDNF leads to targeted reduced GABAergic signaling through autophagic dysregulation of p62, potentially underlying cognitive impairment across brain conditions.

脑源性神经营养因子 (BDNF) 和 γ-氨基丁酸 (GABA) 神经传递减少在脑部疾病（抑郁症、精神分裂症和与年龄相关的疾病）中同时发生，并与症状相关。啮齿动物研究表明它们存在因果关系，表明存在介导这种联系的生物途径。在这里，我们首先表明减少的 BDNF 和 GABA 也与人类抑郁症中的自噬减弱同时发生。然后，我们使用小鼠表明，降低 Bdnf 水平 ( Bdnf ^+/- ) 会导致上调 sequestosome-1/p62，这是一种关键的自噬相关衔接蛋白，其水平与自噬活性呈负相关。降低的 Bdnf 水平还导致含有 α5 亚基的 GABA _A受体（α5-GABA _AR) 在前额叶皮层 (PFC) 锥体神经元中。减少p62基因剂量可恢复 α5-GABA AR 表面表达并挽救 Bdnf _+/-^小鼠的 PFC 相关行为缺陷，包括认知不灵活和减少的感觉运动门控。增加 p62 水平足以重建Bdnf ^+/-小鼠的分子和行为特征。总的来说，这些数据揭示了一种新的机制，通过这种机制，BDNF 缺陷会通过 p62 的自噬失调导致靶向减少的 GABAergic 信号，这可能是跨大脑疾病的潜在认知障碍。