BDNF controls cognitive processes related to neuropsychiatric manifestations via autophagic regulation of p62 and GABAA receptor trafficking

Reduced BDNF and GABAergic inhibition co-occur in neuropsychiatric diseases, including major depression. Genetic rodent studies show a causal link, suggesting the presence of biological pathways that mediate this co-occurrence. Here we show that mice with reduced Bdnf ( Bdnf +/-) have upregulated expression of sequestosome-1/p62, an autophagy-associated stress response protein, and reduced surface presentation of α5 subunit-containing GABAA receptor (α5-GABAAR) in prefrontal cortex (PFC) pyramidal neurons. Reducing p62 gene dosage restored α5-GABAAR surface expression and rescued the PFC-relevant behavioral deficits of Bdnf +/- mice, including cognitive inflexibility and sensorimotor gating deficits. Increasing p62 levels was sufficient to recreate the molecular and behavioral profiles of Bdnf +/- mice. Finally, human postmortem corticolimbic transcriptome analysis suggested reduced autophagic activity in depression. Collectively, the data reveal that autophagy regulation through control of p62 dosage may serve as a mechanism linking reduced BDNF signaling, GABAergic deficits, and psychopathology associated with PFC functional deficits across psychiatric disorders. HIGHLIGHTS BDNF constitutively promotes autophagy in cortical pyramidal neurons Reduced BDNF causes elevated autophagy-regulator p62 expression, leading to lower surface α5-GABAAR presentation Increasing p62 levels mimics cognition-related behavioral deficits in Bdnf +/- mice Altered postmortem corticolimbic gene expression suggests reduced autophagic activity in depression