RT Journal Article
SR Electronic
T1 Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.27.175349
DO 10.1101/2020.06.27.175349
A1 Shannon Cole
A1 Ramesh Chandra
A1 Maya Harris
A1 Ishan Patel
A1 Torrance Wang
A1 Hyunjae Kim
A1 Leah Jensen
A1 Scott J Russo
A1 Gustavo Turecki
A1 Amy M Gancarz-Kausch
A1 David M Dietz
A1 Mary Kay Lobo
YR 2021
UL http://biorxiv.org/content/early/2021/05/12/2020.06.27.175349.abstract
AB Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. We further show that blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure.Competing Interest StatementThe authors have declared no competing interest.AAVadeno-associated virusesChIPchromatin immunoprecipitationCPPconditioned place preferenceD1-MSNdopamine receptor-1 containing medium spiny neuronsD2-MSNdopamine receptor-2 containing medium spiny neuronsDSM-IVDiagnostic and Statistical Manual of Mental Disorders-IVDIOdouble inverted openDrp1dynamin related protein 1Egr3early growth response factor 3Egr3-miREgr3 microRNAIACUCInstitutional Animal Care and Use CommitteeMfn1Mitofusin 1Mfn2Mitofusin 2MSNsmedium spiny neuronsNAcNucleus accumbensOpa1Optic atrophy 1 (alternative: OPA1 mitochondrial dynamin like GTPase)PBSphosphate buffered salinePGC1αperoxisome proliferator-activated receptor gamma coactivatorPolγmitochondrial DNA polymerase subunit gammaNrf1transcription factors nuclear respiratory factor 1Nrf2transcription factors nuclear respiratory factor 2qRT-PCRquantitative real time polymerase chain reactionRTRiboTagSS-miRscramble sequence microRNATfammitochondria-specific transcription factor aTfb1mitochondria-specific transcription factor bTomm20translocase of the outer mitochondrial membrane 20