Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation

Molecular Brain

Mary Kay Lobo¹  Torrance Wang¹  Ishan Patel¹  Ramesh Chandra¹  Maya Harris¹  Hyunjae Kim¹  Leah Jensen¹  Shannon L. Cole¹  David M. Dietz²  Amy M. Gancarz-Kausch³  Scott J. Russo⁴  Gustavo Turecki⁵ 

[1] Department of Anatomy and Neurobiology, University of Maryland School of Medicine, HSF II Rm S265, 20 Penn Street, 21201, Baltimore, MD, USA;Department of Pharmacology and Toxicology, The Research Institution On Addictions, State University of New York At Buffalo, Buffalo, NY, USA;Department of Pharmacology and Toxicology, The Research Institution On Addictions, State University of New York At Buffalo, Buffalo, NY, USA;Department of Psychology, California State University, Bakersfield, Bakersfield, CA, USA;Fishberg Department of Neuroscience and Friedman Brain Institute, Graduate School of Biomedical Sciences At the Icahn School of Medicine At Mount Sinai, New York, NY, USA;McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montréal, QC, Canada;

关键词: Cocaine;    D1-MSNs;    D2-MSNs;    Mitochondria;    Nucleus accumbens;   

DOI  :  10.1186/s13041-021-00800-y

来源: Springer

【 摘 要 】

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. Further, 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.

【 授权许可】

CC BY