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bioRxiv · 10.1101/334466

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

Tomoda, T.·Sumitomo, A.·Hirota-Tsuyada, Y.·Miyachi, H.·Oh, H.·French, L.·Sibille, E.
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Abstract

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 5 subunit-containing GABAA receptor (5-GABAAR) in prefrontal cortex (PFC) pyramidal neurons. Reducing p62 gene dosage restored 5-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.\n\nHIGHLIGHTSBDNF constitutively promotes autophagy in cortical pyramidal neurons\n\nReduced BDNF causes elevated autophagy-regulator p62 expression, leading to lower surface 5-GABAAR presentation\n\nIncreasing p62 levels mimics cognition-related behavioral deficits in Bdnf+/- mice\n\nAltered postmortem corticolimbic gene expression suggests reduced autophagic activity in depression

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Tomoda, T., Sumitomo, A., Hirota-Tsuyada, Y., Miyachi, H., Oh, H., French, L., Sibille, E.. 2018-05-30. BDNF controls neuropsychiatric manifestation via autophagic regulation of p62 and GABAA receptor trafficking. https://doi.org/10.1101/334466

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