Priority CommunicationTranscription Factor E2F3a in Nucleus Accumbens Affects Cocaine Action via Transcription and Alternative Splicing
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Methods and Materials
See also Supplemental Methods and Materials in Supplement 1.
Repeated Cocaine Administration Increases E2f3a mRNA and E2F3a Nuclear Protein Levels in NAc
We probed isoform-specific expression of E2f3 mRNA in NAc following 7 days of 20 mg/kg cocaine (24 hours after final injection). We observed a cocaine-induced increase in E2f3a mRNA levels (main effect of treatment: F1,20 = 12.99, p = .0018, post hoc, E2f3a: p = .0207, E2f3b: p = .0512) (Figure 1D) and a nonsignificant trend for induction of E2f3b. We next investigated the effects of repeated cocaine administration on E2F3a and E2F3b protein levels and subcellular localization. We observed an
Discussion
Our findings provide direct evidence for the role of E2F3a as a key regulator of cocaine-elicited molecular actions via transcriptional regulation and splicing mechanisms. We identified E2f3 as a novel target of cocaine. Repeated cocaine exposure increased E2f3a mRNA expression in NAc and increased E2F3a protein levels in the nucleus. This positions E2F3a to bind DNA and regulate the observed changes in gene expression and RNA processing. The isoform-specific role of E2F3a was further confirmed
Acknowledgments and Disclosures
This work was supported by grants from the National Institute on Drug Abuse Grant Nos. R01DA007359 and P01DA008227 (to EJN).
Author contributions following CRediT Taxonomy are as follows: Conceptualization, HMC and EJN; Methodology, HMC and EJN; Software, IP and LS; Formal Analysis, HMC and IP; Investigation, HMC, EAH, RCB, CKL, CJP, DMW, and MEC; Resources, RLN; Writing—Original Draft, HMC; Writing—Review and Editing, HMC, EAH, CKL, CJP, DMW, RCB, and EJN; Supervision, LS, RCB, and EJN; Funding
References (43)
- et al.
Decoding the epigenetic language of neuronal plasticity
Neuron
(2008) - et al.
Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum
Neuron
(2005) - et al.
Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins
Neuron
(2009) - et al.
Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli
Neuron
(2007) - et al.
Epigenetic mechanisms in drug addiction
Trends Mol Med
(2008) - et al.
Opposing regulation of Sox2 by cell-cycle effectors E2f3a and E2f3b in neural stem cells
Cell Stem Cell
(2013) - et al.
Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility
Neuron
(2016) - et al.
Rapid and stable gene expression in hippocampal slice cultures from a defective HSV-1 vector
Brain Res Mol Brain Res
(1994) - et al.
Bidirectional synaptic structural plasticity after chronic cocaine administration occurs through Rap1 small GTPase signaling
Neuron
(2016) - et al.
Cocaine interacts with the novelty-seeking trait to modulate FGFR1 gene expression in the rat
Neurosci Lett
(2008)
Neonatal fibroblast growth factor treatment enhances cocaine sensitization
Pharmacol Biochem Behav
Organization of the human gene encoding heterogeneous nuclear ribonucleoprotein type I (hnRNP I) and characterization of hnRNP I related pseudogene
Gene
The neural basis of addiction: A pathology of motivation and choice
Am J Psychiatry
Review. Transcriptional mechanisms of addiction: Role of DeltaFosB
Philos Trans R Soc Lond B Biol Sci
Opposing role for Egr3 in nucleus accumbens cell subtypes in cocaine action
J Neurosci
Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward
J Neurosci
Serum response factor and cAMP response element binding protein are both required for cocaine induction of ΔFosB
J Neurosci
Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice
J Neurosci
A phosphatase cascade by which rewarding stimuli control nucleosomal response
Nature
Chronic cocaine-regulated epigenomic changes in mouse nucleus accumbens
Genome Biol
Identification of E2F-3B, an alternative form of E2F-3 lacking a conserved N-terminal region
Oncogene
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EAH is currently affiliated with the Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; MEC is currently affiliated with the Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin; and RCB is currently affiliated with the Department of Psychology, McGill University, Montréal, Québec, Canada.