Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation

Abstract

<jats:title>Abstract</jats:title><jats:p>Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrated that cocaine affects mitochondrial dynamics within the nucleus accumbens (NAc) and mitochondria are differentially regulated by cocaine in dopamine receptor-1 (D1) containing medium spiny neurons (MSNs) vs dopamine receptor-2 (D2)-MSNs. Here, it is demonstrated that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Further, 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 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. Subsequent experiments demonstrated that Egr3 overexpression in D1-MSNs enhances the expression of several mitochondrial-associated nuclear genes. By contrast, blunting Egr3 expression 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, reducing Egr3 expression attenuates the cocaine-induced enhancement of small-sized mitochondria, demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts and mitochondrial dynamics, with implications for mechanisms underlying neuronal function and plasticity occurring with cocaine exposure.</jats:p>

From Circuits to Chromatin: The Emerging Role of Epigenetics in Mental Health

“…Furthermore, enhancement of PGC-1a in either D1-MSNs or D2-MSNs bidirectionally altered cocaine-induced behaviors (R. Chandra et al, 2017b). Consistent with its role in regulating these transcriptional targets, genetic disruption of Egr3 in D1-MSNs was shown to prevent cocaine-induced mitochondrial fission in these neurons (Cole et al, 2020).…”

“…Li et al, 2010;Cheng et al, 2012;R. Chandra et al, 2017b;Divakaruni et al, 2018;Cole et al, 2020). Circuit-specific reduction of Drp1 expression in D1-MSNs resulted in markedly lowered drug-seeking behavior after cocaine self-administration.…”