RGS4 Actions in Mouse Prefrontal Cortex Modulate Behavioral and Transcriptomic Responses to Chronic Stress and Ketamine.

Autor:	Mitsi V; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Ruiz A; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Polizu C; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Farzinpour Z; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Ramakrishnan A; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Serafini RA; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Parise EM; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Floodstrand M; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Sial OK; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Gaspari S; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Tang CY; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Nestler EJ; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Schmidt EF; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Shen L; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.)., Zachariou V; Nash Family Department of Neuroscience and Friedman Brain Institute (V.M., A.Ru., C.P., A.Ra., R.A.S., E.M.P. M.F., S.G., E.J.N., L.S.) and BioMedical Engineering and Imaging Institute (C.Y.T.), Icahn School of Medicine at Mount Sinai, New York, New York; University of Crete, Department of Basic Sciences, Crete, Greece (V.M.); Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts (Z.F., R.A.S., V.Z.); Department of Psychology, Texas A&M University, College Station, Texas (O.K.S.); and Laboratory of Molecular Biology, Rockefeller University, New York, New York (E.F.S.) vzachar@bu.edu.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2024 Mar 14; Vol. 105 (4), pp. 272-285. Date of Electronic Publication: 2024 Mar 14.
DOI:	10.1124/molpharm.123.000753
Abstrakt:	The signal transduction protein, regulator of G protein signaling 4 (RGS4), plays a prominent role in physiologic and pharmacological responses by controlling multiple intracellular pathways. Our earlier work identified the dynamic but distinct roles of RGS4 in the efficacy of monoamine-targeting versus fast-acting antidepressants. Using a modified chronic variable stress (CVS) paradigm in mice, we demonstrate that stress-induced behavioral abnormalities are associated with the downregulation of RGS4 in the medial prefrontal cortex (mPFC). Knockout of RGS4 (RGS4KO) increases susceptibility to CVS, as mutant mice develop behavioral abnormalities as early as 2 weeks after CVS resting-state functional magnetic resonance imaging I (rs-fMRI) experiments indicate that stress susceptibility in RGS4KO mice is associated with changes in connectivity between the mediodorsal thalamus (MD-THL) and the mPFC. Notably, RGS4KO also paradoxically enhances the antidepressant efficacy of ketamine in the CVS paradigm. RNA-sequencing analysis of naive and CVS samples obtained from mPFC reveals that RGS4KO triggers unique gene expression signatures and affects several intracellular pathways associated with human major depressive disorder. Our analysis suggests that ketamine treatment in the RGS4KO group triggers changes in pathways implicated in synaptic activity and responses to stress, including pathways associated with axonal guidance and myelination. Overall, we show that reducing RGS4 activity triggers unique gene expression adaptations that contribute to chronic stress disorders and that RGS4 is a negative modulator of ketamine actions. SIGNIFICANCE STATEMENT: Chronic stress promotes robust maladaptation in the brain, but the exact intracellular pathways contributing to stress vulnerability and mood disorders have not been thoroughly investigated. In this study, the authors used murine models of chronic stress and multiple methodologies to demonstrate the critical role of the signal transduction modulator regulator of G protein signaling 4 in the medial prefrontal cortex in vulnerability to chronic stress and the efficacy of the fast-acting antidepressant ketamine. (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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