The role of dendritic bdnf transcripts on altered inhibitory circuitry in aging and depression

TL;DR: A mechanistic link between the GABA and neurotrophic hypotheses of major depression is provided, which data indicate may be through dysfunctional dendritic-targeting interneuron populations.

Abstract: Low neurotrophic support and a GABA deficit have been suggested as mechanisms underlying structural and functional abnormalities of the brain in depressed subjects. A parallel downregulation of brain-derived neurotrophic factor (BDNF) and GABA function-related genes including somatostatin (SST), a marker of GABA interneurons targeting the dendritic compartment of pyramidal cells, has been consistently observed during normal aging and in major depression. Here, translational research combining cell culture, animal and human postmortem studies has been conducted in search of a possible link between BDNF and GABA interneurons. I found that dendritic-targeting interneuron markers displayed a higher BDNF dependency compared to other GABAergic genes in BDNF-knockdown mice. To explore the nature and extent of the biological components linking BDNF and SST, we analyzed the top 200 genes positively correlated with BDNF expression in the human brain and found that age-related BDNF reduction may induce synaptic alterations which are likely responsible for age-associated cognitive decline. Interestingly, SST and the α5 subunit of GABAA receptor (GABRA5), a subunit considered to be enriched in the post-synaptic compartment of SST (+) interneurons, are included in the top 200 genes, with GABRA5 displaying the highest correlation with BDNF expression among ~ 300,000 probes examined with the arrays. These data suggest that the synaptic target of SST (+) interneurons, the distal dendrite, may act as a bridge between BDNF and SST. Therefore, we hypothesized that MDD is associated with reduced dendritic BDNF which results in low BDNF supply to SST (+) interneurons. Indeed, 3’ untranslated region (UTR)-containing-BDNF mRNA, which is known to migrate to the distal dendrites of pyramidal cells, showed downregulation in the dorsolateral prefrontal cortex (dlPFC) of depressed subjects and medial prefrontal cortex of stressed mice. Furthermore, such changes were closely linked to changes in dendritic-targeting interneuron markers. Knockdown of BDNF long 3’ UTR was sufficient to induce dendritic shrinkage, depressive-/anxiety-like behavior, and SST downregulation. Finally, pharmacological potentiation of TrkB prevented the development of depression-like behaviors following chronic stress in rodents. Together, I provide a mechanistic link between the GABA and neurotrophic hypotheses of major depression, which data indicate may be through dysfunctional dendritic-targeting interneuron populations.