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THE ROLE OF DENDRITIC BRAIN-DERIVED NEUROTROPHIC FACTOR TRANSCRIPTS ON ALTERED INHIBITORY CIRCUITRY IN DEPRESSION

By Hyunjung Oh, Sean C Piantadosi, Brad R Rocco, David A. Lewis, Simon C. Watkins, Etienne Sibille

Posted 30 May 2018
bioRxiv DOI: 10.1101/333294 (published DOI: 10.1016/j.biopsych.2018.09.026)

Background: A parallel downregulation of brain-derived neurotrophic factor (BDNF) and somatostatin (SST), a marker of inhibitory gamma-amino-butyric acid (GABA) interneurons which target pyramidal cell dendrites, has been reported in several brain areas of subjects with major depressive disorder (MDD), and rodent genetic studies suggests they are linked and both contribute to the illness. However, the mechanism by which they contribute to the pathophysiology of the illness has remained elusive. Methods: With qPCR, we determined the expression level of BDNF transcript variants and synaptic markers in the prefrontal cortex (PFC) of MDD patients and matched controls (n=19/group) and of C57BL/6J mice exposed to chronic stress or control conditions (n=12/group). We next suppressed BDNF transcripts with long 3 primer untranslated region (L-3-UTR) using small hairpin RNA (shRNA) and investigated changes in cell morphology, gene expression and behavior. Results: L-3-UTR containing BDNF mRNAs, which migrate to distal dendrites of pyramidal neurons, are selectively reduced and highly correlated with SST expression in the PFC of MDD subjects. A similar downregulation occurs in mice submitted to chronic stress. We next show that Bdnf L-3-UTR knockdown is sufficient to induce (i) dendritic shrinkage in cortical neurons, (ii) cell-specific MDD-like gene changes (including Sst downregulation), and (iii) depressive-/anxiety-like behaviors. The translational validity of the Bdnf L-3-UTR shRNA-treated mice was confirmed by significant cross-species correlation of changes in MDD-associated gene expression. Conclusion: These findings provide evidence for a novel MDD-related pathological mechanism linking local neurotrophic support, pyramidal cell structure, dendritic inhibition and mood regulation.

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