Rxivist logo

BDNF controls neuropsychiatric manifestation via autophagic regulation of p62 and GABAA receptor trafficking

By Toshifumi Tomoda, Akiko Sumitomo, Rammohan Shukla, Yuki Hirota-Tsuyada, Hitoshi Miyachi, Hyunjung Oh, Leon French, Etienne Sibille

Posted 30 May 2018
bioRxiv DOI: 10.1101/334466

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.

Download data

  • Downloaded 1,055 times
  • Download rankings, all-time:
    • Site-wide: 27,572
    • In neuroscience: 3,409
  • Year to date:
    • Site-wide: 85,285
  • Since beginning of last month:
    • Site-wide: 68,586

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide