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

SummaryReduced 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.HIGHLIGHTSBDNF constitutively promotes autophagy in cortical pyramidal neuronsReduced BDNF causes elevated autophagy-regulator p62 expression, leading to lower surface α5-GABAAR presentationIncreasing p62 levels mimics cognition-related behavioral deficits in Bdnf+/- miceAltered postmortem corticolimbic gene expression suggests reduced autophagic activity in depression