The stress-induced transcription factor NR4A1 adjusts mitochondrial function and synapse number in prefrontal cortex.

Freddy Jeanneteau, Christian Barrère, Mariska Vos, Carlie J.M. De Vries, Claude Rouillard, Daniel Levesque, Yann Dromard, Marie-Pierre Moisan, Vanja Duric, Tina C. Franklin, Ronald S. Duman, David A. Lewis, Stephen D. Ginsberg, Margarita Arango-Lievano
J. Neurosci.. 2018-01-02; 38(6): 1335-1350
DOI: 10.1523/jneurosci.2793-17.2017

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1. J Neurosci. 2018 Feb 7;38(6):1335-1350. doi: 10.1523/JNEUROSCI.2793-17.2017. Epub
2018 Jan 2.

The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and
Synapse Number in Prefrontal Cortex.

Jeanneteau F(1), Barrère C(2), Vos M(3), De Vries CJM(3), Rouillard C(4),
Levesque D(5), Dromard Y(2), Moisan MP(6), Duric V(7), Franklin TC(8), Duman
RS(8), Lewis DA(9), Ginsberg SD(10)(11), Arango-Lievano M(1).

Author information:
(1)Département de Neuroscience et Physiologie, Institut de Génomique
Fonctionnelle, Institut National de la Santé et de la Recherche Médicale, Centre
National de Recherche Scientifique, Université de Montpellier, Montpellier, 34090
France, .
(2)Département de Neuroscience et Physiologie, Institut de Génomique
Fonctionnelle, Institut National de la Santé et de la Recherche Médicale, Centre
National de Recherche Scientifique, Université de Montpellier, Montpellier, 34090
(3)Department of Medical Biochemistry, Academic Medical Center, University of
Amsterdam, 1012 WX Amsterdam, The Netherlands.
(4)Département de Psychiatrie et Neuroscience, Université Laval, Québec City,
Québec G1V 0A6, Canada.
(5)Faculté de Pharmacie, Université de Montréal, Montréal, Québec H3T 1J4,
(6)Nutrition and Integrative Neurobiology, Institut National de la Recherche
Agronomique, Université de Bordeaux, 33076 Bordeaux, France.
(7)Department of Physiology and Pharmacology, Des Moines University, Des Moines,
Iowa 50312.
(8)Department of Psychiatry and Neurobiology, Yale University, New Haven,
Connecticut 06520.
(9)Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
(10)The Nathan S. Kline Institute for Pyschiatric Research, Orangeburg, New York
10962, and.
(11)Department of Psychiatry, Neuroscience & Physiology, NYU Langone Medical
Center, New York, New York 10016.

The energetic costs of behavioral chronic stress are unlikely to be sustainable
without neuronal plasticity. Mitochondria have the capacity to handle synaptic
activity up to a limit before energetic depletion occurs. Protective mechanisms
driven by the induction of neuronal genes likely evolved to buffer the
consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC),
as this circuitry is vulnerable to excitotoxic insults. Little is known about the
genes involved in mitochondrial adaptation to the buildup of chronic stress.
Using combinations of genetic manipulations and stress for analyzing structural,
transcriptional, mitochondrial, and behavioral outcomes, we characterized NR4A1
as a stress-inducible modifier of mitochondrial energetic competence and
dendritic spine number in PFC. NR4A1 acted as a transcription factor for changing
the expression of target genes previously involved in mitochondrial uncoupling,
AMP-activated protein kinase activation, and synaptic growth. Maintenance of
NR4A1 activity by chronic stress played a critical role in the regressive
synaptic organization in PFC of mouse models of stress (male only). Knockdown,
dominant-negative approach, and knockout of Nr4a1 in mice and rats (male only)
protected pyramidal neurons against the adverse effects of chronic stress. In
human PFC tissues of men and women, high levels of the transcriptionally active
NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the
context of chronic stress, prolonged expression and activity of NR4A1 may lead to
responses of mitochondria and synaptic connectivity that do not match
environmental demand, resulting in circuit malfunction between PFC and other
brain regions, constituting a pathological feature across disorders.SIGNIFICANCE
STATEMENT The bioenergetic cost of chronic stress is too high to be sustainable
by pyramidal prefrontal neurons. Cellular checkpoints have evolved to adjust the
responses of mitochondria and synapses to the buildup of chronic stress. NR4A1
plays such a role by controlling the energetic competence of mitochondria with
respect to synapse number. As an immediate-early gene, Nr4a1 promotes neuronal
plasticity, but sustained expression or activity can be detrimental. NR4A1
expression and activity is sustained by chronic stress in animal models and in
human studies of neuropathologies sensitive to the buildup of chronic stress.
Therefore, antagonism of NR4A1 is a promising avenue for preventing the
regressive synaptic reorganization in cortical systems in the context of chronic

Copyright © 2018 Wu, Lee et al.

DOI: 10.1523/JNEUROSCI.2793-17.2017
PMCID: PMC5815341
PMID: 29295823

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