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THE ROLE OF DENDRITIC BDNF TRANSCRIPTS ON ALTERED INHIBITORY CIRCUITRY IN AGING AND DEPRESSION

Oh, Hyunjung (2015) THE ROLE OF DENDRITIC BDNF TRANSCRIPTS ON ALTERED INHIBITORY CIRCUITRY IN AGING AND DEPRESSION. Doctoral Dissertation, University of Pittsburgh.

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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.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Oh, Hyunjunghyo2@pitt.eduHYO2
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBradberry, Charlesbradberr@pitt.eduBRADBERR
Thesis AdvisorSibille, Etienneetienne.sibille@camh.ca
Committee MemberErickson, Kirk Ikiericks@pitt.eduKIERICKS
Committee MemberRinaman, Lindarinaman@pitt.eduRINAMAN
Committee MemberHastings, Teresahastingst@upmc.eduTHASTING
Committee MemberLee, Francisfslee@med.cornell.edu
Date: 2 December 2015
Date Type: Publication
Defense Date: 11 September 2015
Approval Date: 2 December 2015
Submission Date: 19 November 2015
Release Date: 2 December 2015
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 202
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: BDNF, dendrite, SST, GABA, interneuron
Date Deposited: 02 Dec 2015 15:25
Last Modified: 19 Dec 2016 14:42
URI: http://d-scholarship.pitt.edu/id/eprint/26371

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