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Cyclin-Dependent Kinase 5 Dysfunction Contributes to Depressive-like Behaviors in Huntington’s Disease by Altering the DARPP-32 Phosphorylation Status in the Nucleus Accumbens

  • Veronica Brito
    Affiliations
    Department of Biomedical Science, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
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  • Albert Giralt
    Affiliations
    Department of Biomedical Science, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
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  • Mercè Masana
    Affiliations
    Department of Biomedical Science, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
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  • Aida Royes
    Affiliations
    Department of Biomedical Science, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
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  • Marc Espina
    Affiliations
    Department of Biomedical Science, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
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  • Esther Sieiro
    Affiliations
    Department of Biomedical Science, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
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  • Jordi Alberch
    Affiliations
    Department of Biomedical Science, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
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  • Anna Castañé
    Affiliations
    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Department of Neurochemistry and Neuropharmacology, CSIC-Institut d’Investigacions Biomèdiques de Barcelona, Barcelona, Spain

    Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain
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  • Jean-Antoine Girault
    Affiliations
    Inserm UMR-S 839, Paris, France

    Sorbonne Université, Paris, France

    Institut du Fer a Moulin, Paris, France
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  • Silvia Ginés
    Correspondence
    Address correspondence to Silvia Ginés, Ph.D., Department of Biomedical Science, Faculty of Medicine, University of Barcelona, Casanova 143, Barcelona 08036, Spain.
    Affiliations
    Department of Biomedical Science, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
    Search for articles by this author

      Abstract

      Background

      Depression is the most common psychiatric condition in Huntington’s disease (HD), with rates more than twice those found in the general population. At the present time, there is no established molecular evidence to use as a basis for depression treatment in HD. Indeed, in some patients, classic antidepressant drugs exacerbate chorea or anxiety. Cyclin-dependent kinase 5 (Cdk5) has been involved in processes associated with anxiety and depression. This study evaluated the involvement of Cdk5 in the development and prevalence of depressive-like behaviors in HD and aimed to validate Cdk5 as a target for depression treatment.

      Methods

      We evaluated the impact of pharmacological inhibition of Cdk5 in depressive-like and anxiety-like behaviors in Hdh+/Q111 knock-in mutant mice by using a battery of behavioral tests. Biochemical and morphological studies were performed to define the molecular mechanisms acting downstream of Cdk5 activation. A double huntingtin/DARPP-32 (dopamine- and cAMP-regulated phosphoprotein 32) knock-in mutant mouse was generated to analyze the role of DARPP-32 in HD depression.

      Results

      We found that Hdh+/Q111 mutant mice exhibited depressive-like, but not anxiety-like, behaviors starting at 2 months of age. Cdk5 inhibition by roscovitine infusion prevented depressive-like behavior and reduced DARPP-32 phosphorylation at Thr75 in the nucleus accumbens. Hdh+/Q111 mice heterozygous for DARPP-32 Thr75Ala point mutation were resistant to depressive-like behaviors. We identified β-adducin phosphorylation as a Cdk5 downstream mechanism potentially mediating structural spine plasticity changes in the nucleus accumbens and depressive-like behavior.

      Conclusions

      These results point to Cdk5 in the nucleus accumbens as a critical contributor to depressive-like behaviors in HD mice by altering DARPP-32/β-adducin signaling and disrupting the dendritic spine cytoskeleton.

      Keywords

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      References

        • Van Duijn E.
        • Craufurd D.
        • Hubers A.A.M.
        • Giltay E.J.
        • Bonelli R.
        • Rickards H.
        • et al.
        Neuropsychiatric symptoms in a European Huntington’s disease cohort (REGISTRY).
        J Neurol Neurosurg Psychiatry. 2014; 85: 1411-1418
        • Ho A.K.
        • Gilbert A.S.
        • Mason S.L.
        • Goodman A.O.
        • Barker R.A.
        Health-related quality of life in Huntington’s disease: Which factors matter most?.
        Mov Disord. 2009; 24: 574-578
        • Chari S.
        • Quraishi S.H.
        • Jainer A.K.
        Fluoxetine-induced exacerbation of chorea in Huntington’s disease? A case report.
        Pharmacopsychiatry. 2003; 36: 41-43
        • Novak M.J.
        • Tabrizi S.J.
        Huntington’s disease: Clinical presentation and treatment.
        Int Rev Neurobiol. 2011; 98: 297-323
        • Su S.C.
        • Tsai L.H.
        Cyclin-dependent kinases in brain development and disease.
        Annu Rev Cell Dev Biol. 2011; 27: 465-491
        • Gilmore E.C.
        • Ohshima T.
        • Goffinet A.M.
        • Kulkarni A.B.
        • Herrup K.
        Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex.
        J Neurosci. 1998; 18: 6370-6377
        • Ko J.
        • Humbert S.
        • Bronson R.T.
        • Takahashi S.
        • Kulkarni A.B.
        • Li E.
        • Tsai L.H.
        P35 and P39 are essential for cyclin-dependent kinase 5 function during neurodevelopment.
        J Neurosci. 2001; 21: 6758-6771
        • Rakić S.
        • Davis C.
        • Molnár Z.
        • Nikolić M.
        • Parnavelas J.G.
        Role of p35/Cdk5 in preplate splitting in the developing cerebral cortex.
        Cereb Cortex. 2006; 16: i35-i45
        • Cheung Z.H.
        • Fu A.K.
        • Ip N.Y.
        Synaptic roles of Cdk5: Implications in higher cognitive functions and neurodegenerative diseases.
        Neuron. 2006; 50: 13-18
        • Barnett D.G.
        • Bibb J.A.
        The role of Cdk5 in cognition and neuropsychiatric and neurological pathology.
        Brain Res Bull. 2011; 85: 9-13
        • Paoletti P.
        • Vila I.
        • Rife M.
        • Lizcano J.M.
        • Alberch J.
        • Gines S.
        Dopaminergic and glutamatergic signaling crosstalk in Huntington’s disease neurodegeneration: The role of p25/cyclin-dependent kinase 5.
        J Neurosci. 2008; 28: 10090-10101
        • Alvarez-Periel E.
        • Puigdellívol M.
        • Brito V.
        • Plattner F.
        • Bibb J.A.
        • Alberch J.
        • Ginés S.
        Cdk5 contributes to Huntington’s disease learning and memory deficits via modulation of brain region-specific substrates.
        Mol Neurobiol. 2018; 55: 6250-6268
        • Papadopoulou A.
        • Siamatras T.
        • Delgado-Morales R.
        • Amin N.D.
        • Shukla V.
        • Zheng Y.L.
        • et al.
        Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression.
        Transl Psychiatry. 2015; 5: e578
        • Li G.
        • Liu T.
        • Kong X.
        • Wang L.
        • Jin X.
        Hippocampal glycogen synthase kinase 3β is critical for the antidepressant effect of cyclin-dependent kinase 5 inhibitor in rats.
        J Mol Neurosci. 2014; 54: 92-99
        • Zhu W.L.
        • Shi H.S.
        • Wang S.J.
        • Xu C.M.
        • Jiang W.G.
        • Wang X.
        • et al.
        Increased Cdk5/p35 activity in the dentate gyrus mediates depressive-like behaviour in rats.
        Int J Neuropsychopharmacol. 2012; 15: 795-809
        • Su S.C.
        • Rudenko A.
        • Cho S.
        • Tsai L.H.
        Forebrain-specific deletion of Cdk5 in pyramidal neurons results in mania-like behavior and cognitive impairment.
        Neurobiol Learn Mem. 2013; 105: 54-62
        • Plattner F.
        • Hayashi K.
        • Hernández A.
        • Benavides D.R.
        • Tassin T.C.
        • Tan C.
        • et al.
        The role of ventral striatal cAMP signaling in stress-induced behaviors.
        Nat Neurosci. 2015; 18: 1094-1100
        • Zhong P.
        • Liu X.
        • Zhang Z.
        • Hu Y.
        • Liu S.J.
        • Lezama-Ruiz M.
        • et al.
        Cyclin-dependent kinase 5 in the ventral tegmental area regulates depression-related behaviors.
        J Neurosci. 2014; 34: 6352-6366
        • Wheeler V.C.
        • Auerbach W.
        • White J.K.
        • Srinidhi J.
        • Auerbach A.
        • Ryan A.
        • et al.
        Length-dependent gametic CAG repeat instability in the Huntington’s disease knock-in mouse.
        Hum Mol Genet. 1999; 8: 115-122
        • Lloret A.
        • Dragileva E.
        • Teed A.
        • Espinola J.
        • Fossale E.
        • Gillis T.
        • et al.
        Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington’s disease knock-in mice.
        Hum Mol Genet. 2006; 15: 2015-2024
        • Svenningsson P.
        • Tzavara E.T.
        • Carruthers R.
        • Rachleff I.
        • Wattler S.
        • Nehls M.
        • et al.
        Diverse psychotomimetics act through a common signaling pathway.
        Science. 2003; 302: 1412-1415
        • Crews L.
        • Patrick C.
        • Adame A.
        • Rockenstein E.
        • Masliah E.
        Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer’s disease.
        Cell Death Dis. 2011; 2: e120
        • Brito V.
        • Giralt A.
        • Enriquez-Barreto L.
        • Puigdellívol M.
        • Suelves N.
        • Zamora-Moratalla A.
        • et al.
        Neurotrophin receptor p75 NTR mediates Huntington’s disease–associated synaptic and memory dysfunction.
        J Clin Invest. 2014; 124: 4411-4428
        • Duff K.
        • Paulsen J.
        • Mills J.
        • Beglinger L.J.
        • Moser D.J.
        • Smith M.M.
        • et al.
        Mild cognitive impairment in prediagnosed Huntington disease.
        Neurology. 2010; 75: 500-507
        • Julien C.L.
        • Thompson J.C.
        • Wild S.
        • Yardumian P.
        • Snowden J.S.
        • Turner G.
        • Craufurd D.
        Psychiatric disorders in preclinical Huntington’s disease.
        J Neurol Neurosurg Psychiatry. 2007; 78: 939-943
        • Kingma E.M.
        • van Duijn E.
        • Timman R.
        • van der Mast R.C.
        • Roos R.A.
        Behavioural problems in Huntington’s disease using the Problem Behaviours Assessment.
        Gen Hosp Psychiatry. 2008; 30: 155-161
        • Pla P.
        • Orvoen S.
        • Saudou F.
        • David D.J.
        • Humbert S.
        Mood disorders in Huntington’s disease: from behavior to cellular and molecular mechanisms.
        Front Behav Neurosci. 2014; 8: 135
        • Krishnan V.
        • Nestler E.J.
        The molecular neurobiology of depression.
        Nature. 2008; 455: 894-902
        • Puigdellívol M.
        • Cherubini M.
        • Brito V.
        • Giralt A.
        • Suelves N.
        • Ballesteros J.
        • et al.
        A role for Kalirin-7 in corticostriatal synaptic dysfunction in Huntington’s disease.
        Hum Mol Genet. 2015; 24: 7265-7285
        • Suelves N.
        • Miguez A.
        • López-Benito S.
        • Barriga G.G.-D.
        • Giralt A.
        • Alvarez-Periel E.
        • et al.
        Early downregulation of p75NTR by genetic and pharmacological approaches delays the onset of motor deficits and striatal dysfunction in Huntington’s disease mice.
        Mol Neurobiol. 2019; 56: 935-953
        • Weiss J.M.
        • Goodman P.A.
        • Losito B.G.
        • Corrigan S.
        • Charry J.M.
        • Bailey W.H.
        Behavioral depression produced by an uncontrollable stressor: Relationship to norepinephrine, dopamine, and serotonin levels in various regions of rat brain.
        Brain Res Rev. 1981; 3: 167-205
        • Perona M.T.
        • Waters S.
        • Hall F.S.
        • Sora I.
        • Lesch K.-P.
        • Murphy D.L.
        • et al.
        Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions.
        Behav Pharmacol. 2008; 19: 566-574
        • Nestler E.J.
        • Barrot M.
        • DiLeone R.J.
        • Eisch A.J.
        • Gold S.J.
        • Monteggia L.M.
        Neurobiology of depression.
        Neuron. 2002; 34: 13-25
        • Holmes A.
        • Wellman C.L.
        Stress-induced prefrontal reorganization and executive dysfunction in rodents.
        Neurosci Biobehav Rev. 2009; 33: 773-783
        • Pandya M.
        • Altinay M.
        • Malone D.A.
        • Anand A.
        Where in the brain is depression?.
        Curr Psychiatry Rep. 2012; 14: 634-642
        • Campbell S.
        • MacQueen G.
        The role of the hippocampus in the pathophysiology of major depression.
        J Psychiatry Neurosci. 2004; 29: 417-426
        • Svenningsson P.
        • Tzavara E.T.
        • Witkin J.M.
        • Fienberg A.A.
        • Nomikos G.G.
        • Greengard P.
        Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac).
        Proc Natl Acad Sci U S A. 2002; 99: 3182-3187
        • Bibb J.A.
        • Snyder G.L.
        • Nishi A.
        • Yan Z.
        • Meijer L.
        • Flenberg A.A.
        • et al.
        Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons.
        Nature. 1999; 402: 669-671
        • Bibb J.A.
        • Chen J.
        • Taylor J.R.
        • Svenningsson P.
        • Nishi A.
        • Snyder G.L.
        • et al.
        Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5.
        Nature. 2001; 410: 376-380
        • Francis T.C.
        • Lobo M.K.
        Emerging role for nucleus accumbens medium spiny neuron subtypes in depression.
        Biol Psychiatry. 2017; 81: 645-653
        • Christoffel D.J.
        • Golden S.A.
        • Russo S.J.
        Structural and synaptic plasticity in stress-related disorders.
        Rev Neurosci. 2011; 22: 535-549
        • Duman C.H.
        • Duman R.S.
        Spine synapse remodeling in the pathophysiology and treatment of depression.
        Neurosci Lett. 2014; 601: 20-29
        • Qiao H.
        • Li M.X.
        • Xu C.
        • Chen H.B.
        • An S.C.
        • Ma X.M.
        Dendritic spines in depression: What we learned from animal models.
        Neural Plast. 2016; 2016: 8056370
        • Engmann O.
        • Giralt A.
        • Gervasi N.
        • Marion-Poll L.
        • Gasmi L.
        • Filhol O.
        • et al.
        DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons.
        Nat Commun. 2015; 6: 10099
        • Cauthron R.D.
        • Carter K.B.
        • Liauw S.
        • Steinberg R.A.
        Physiological phosphorylation of protein kinase A at Thr-197 is by a protein kinase A kinase.
        Mol Cell Biol. 1998; 18: 1416-1423
        • Svenningsson P.
        • Nishi A.
        • Fisone G.
        • Girault J.-A.
        • Nairn A.C.
        • Greengard P.
        DARPP-32: An integrator of neurotransmission.
        Annu Rev Pharmacol Toxicol. 2004; 44: 269-296
        • Fernandez É.
        • Schiappa R.
        • Girault J.A.
        • Le Novère N.
        DARPP-32 is a robust integrator of dopamine and glutamate signals.
        PLoS Comput Biol. 2006; 2: 1619-1633
        • Orvoen S.
        • Pla P.
        • Gardier A.M.
        • Saudou F.
        • David D.J.
        Huntington’s disease knock-in male mice show specific anxiety-like behaviour and altered neuronal maturation.
        Neurosci Lett. 2012; 507: 127-132
        • Soylu-Kucharz R.
        • Baldo B.
        • Petersén Å.
        Metabolic and behavioral effects of mutant huntingtin deletion in Sim1 neurons in the BACHD mouse model of Huntington’s disease.
        Sci Rep. 2016; 6: 28322
        • Berrios G.E.
        • Wagle A.C.
        • Marková I.S.
        • Wagle S.A.
        • Ho L.W.
        • Rubinsztein D.C.
        • et al.
        Psychiatric symptoms and CAG repeats in neurologically asymptomatic Huntington’s disease gene carriers.
        Psychiatry Res. 2001; 102: 217-225
        • Craufurd D.
        • Thompson J.C.
        • Snowden J.S.
        Behavioral changes in Huntington disease.
        Neuropsychiatry Neuropsychol Behav Neurol. 2001; 14: 219-226
        • Pouladi M.A.
        • Graham R.K.
        • Karasinska J.M.
        • Xie Y.
        • Santos R.D.
        • Petersn Â.
        • Hayden M.R.
        Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin.
        Brain. 2009; 132: 919-932
        • de Paula Nascimento-Castro C.
        • Wink A.C.
        • da Fônseca V.S.
        • Bianco C.D.
        • Winkelmann-Duarte E.C.
        • Farina M.
        • et al.
        Antidepressant effects of probucol on early-symptomatic YAC128 transgenic mice for Huntington’s disease.
        Neural Plast. 2018; 2018: 4056383
        • da Fonsêca V.S.
        • da Silva Colla A.R.
        • de Paula Nascimento-Castro C.
        • Plácido E.
        • Rosa J.M.
        • Farina M.
        • et al.
        Brain-derived neurotrophic factor prevents depressive-like behaviors in early-symptomatic YAC128 Huntington’s disease mice.
        Mol Neurobiol. 2018; 55: 7201—7215
        • Bragg R.M.
        • Coffey S.R.
        • Weston R.M.
        • Ament S.A.
        • Cantle J.P.
        • Minnig S.
        • et al.
        Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.HttQ111/+ model of Huntington’s disease.
        Sci Rep. 2017; 7: 41570
        • Diehl D.J.
        • Gershon S.
        The role of dopamine in mood disorders.
        Compr Psychiatry. 1992; 33: 115-120
        • Owens M.J.
        • Nemeroff C.B.
        The serotonin transporter and depression.
        Depress Anxiety. 1998; 8: 5-12
        • Murphy D.L.
        • Lesch K.P.
        Targeting the murine serotonin transporter: Insights into human neurobiology.
        Nat Rev Neurosci. 2008; 9: 85-96
        • Hickey M.A.
        • Reynolds G.P.
        • Morton A.J.
        The role of dopamine in motor symptoms in the R6/2 transgenic mouse model of Huntington’s disease.
        J Neurochem. 2002; 81: 46-59
        • Huot P.
        • Hutchison W.D.
        Serotonin/dopamine transporter ratio as a predictor of L-dopa-induced dyskinesia.
        Neurology. 2015; 85: 840-841
        • Mochel F.
        • Durant B.
        • Durr A.
        • Schiffmann R.
        Altered dopamine and serotonin metabolism in motorically asymptomatic R6/2 mice.
        PLoS One. 2011; 6: e18336
        • Chen J.Y.
        • Wang E.A.
        • Cepeda C.
        • Levine M.S.
        Dopamine imbalance in Huntington’s disease: A mechanism for the lack of behavioral flexibility.
        Front Neurosci. 2013; 7: 114
        • Greengard P.
        The neurobiology of slow synaptic transmission.
        Science. 2001; 294: 1024-1030
        • Yamamura Y.
        • Morigaki R.
        • Kasahara J.
        • Yokoyama H.
        • Tanabe A.
        • Okita S.
        • et al.
        Dopamine signaling negatively regulates striatal phosphorylation of Cdk5 at tyrosine 15 in mice.
        Front Cell Neurosci. 2013; 7: 12
        • Chergui K.
        • Svenningsson P.
        • Greengard P.
        Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum.
        Proc Natl Acad Sci U S A. 2004; 101: 2191-2196
        • Gil J.M.
        • Mohapel P.
        • Araújo I.M.
        • Popovic N.
        • Li J.Y.
        • Brundin P.
        • Petersén Å.
        Reduced hippocampal neurogenesis in R6/2 transgenic Huntington’s disease mice.
        Neurobiol Dis. 2005; 20: 744-751
        • Phillips W.
        Abnormalities of neurogenesis in the R6/2 mouse model of Huntington’s disease are attributable to the in vivo microenvironment.
        J Neurosci. 2005; 25: 11564-11576
        • Lazic S.E.
        • Grote H.E.
        • Blakemore C.
        • Hannan A.J.
        • van Dellen A.
        • Phillips W.
        • Barker R.A.
        Neurogenesis in the R6/1 transgenic mouse model of Huntington’s disease: Effects of environmental enrichment.
        Eur J Neurosci. 2006; 23: 1829-1838
        • Henn F.A.
        • Vollmayr B.
        Neurogenesis and depression: Etiology or epiphenomenon?.
        Biol Psychiatry. 2004; 56: 146-150
        • Zuccato C.
        • Liber D.
        • Ramos C.
        • Tarditi A.
        • Rigamonti D.
        • Tartari M.
        • et al.
        Progressive loss of BDNF in a mouse model of Huntington’s disease and rescue by BDNF delivery.
        Pharmacol Res. 2005; 52: 133-139
        • Brito V.
        • Puigdellívol M.
        • Giralt A.
        • Del Toro D.
        • Alberch J.
        • Ginés S.
        Imbalance of p75NTR/TrkB protein expression in Huntington’s disease: Implication for neuroprotective therapies.
        Cell Death Dis. 2013; 4: e595
        • Nguyen K.Q.
        • Rymar V.V.
        • Sadikot A.F.
        Impaired TrkB signaling underlies reduced BDNF-mediated trophic support of striatal neurons in the R6/2 mouse model of Huntington’s disease.
        Front Cell Neurosci. 2016; 10: 37
        • Simmons D.A.
        Modulating neurotrophin receptor signaling as a therapeutic strategy for Huntington’s disease.
        J Huntingtons Dis. 2017; 6: 303-325
        • Martinowich K.
        • Manji H.
        • Lu B.
        New insights into BDNF function in depression and anxiety.
        Nat Neurosci. 2007; 10: 1089-1093
        • Liu F.
        • Ma X.H.
        • Ule J.
        • Bibb J.A.
        • Nishi A.
        • DeMaggio A.J.
        • et al.
        Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors.
        Proc Natl Acad Sci U S A. 2001; 98: 11062-11068
        • Nishi A.
        • Bibb J.A.
        • Snyder G.L.
        • Higashi H.
        • Nairn A.C.
        • Greengard P.
        Amplification of dopaminergic signaling by a positive feedback loop.
        Proc Natl Acad Sci U S A. 2000; 97: 12840-12845
        • Gassen N.C.
        • Fries G.R.
        • Zannas A.S.
        • Hartmann J.
        • Zschocke J.
        • Hafner K.
        • et al.
        Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine.
        Sci Signal. 2015; 8: ra119
        • Zhang Z.
        • Zhang P.
        • Qi G.J.
        • Jiao F.J.
        • Wang Q.Z.
        • Yan J.G.
        • et al.
        CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress.
        Biochim Biophys Acta Mol Basis Dis. 2018; 1864: 533-541
        • Huntington Study Group
        Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial.
        Neurology. 2006; 66: 366-372
        • Jankovic J.
        • Beach J.
        Long-term effects of tetrabenazine in hyperkinetic movement disorders.
        Neurology. 1997; 48: 358-362
        • Nunes E.J.
        • Randall P.A.
        • Hart E.E.
        • Freeland C.
        • Yohn S.E.
        • Baqi Y.
        • et al.
        Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine: implications for animal models of the motivational symptoms of depression.
        J Neurosci. 2013; 33: 19120-19130
        • Christoffel D.J.
        • Golden S.A.
        • Dumitriu D.
        • Robison A.J.
        • Janssen W.G.
        • Ahn H.F.
        • et al.
        IB kinase regulates social defeat stress-induced synaptic and behavioral plasticity.
        J Neurosci. 2011; 31: 314-321
        • Christoffel D.J.
        • Golden S.A.
        • Heshmati M.
        • Graham A.
        • Birnbaum S.
        • Neve R.L.
        • et al.
        Effects of inhibitor of kappaB kinase activity in the nucleus accumbens on emotional behavior.
        Neuropsychopharmacology. 2012; 37: 2615-2623
        • Bessa J.M.
        • Morais M.
        • Marques F.
        • Pinto L.
        • Palha J.A.
        • Almeida O.F.
        • Sousa N.
        Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens.
        Transl Psychiatry. 2013; 3: e266
        • Bharucha K.J.
        • Sethi K.D.
        Complex movement disorders induced by fluoxetine.
        Mov Disord. 1996; 11: 324-326
        • van den Bogaard S.J.
        • Dumas E.M.
        • Acharya T.P.
        • Johnson H.
        • Langbehn D.R.
        • Scahill R.I.
        • et al.
        Early atrophy of pallidum and accumbens nucleus in Huntington’s disease.
        J Neurol. 2011; 258: 412-420
        • Lorenzetti V.
        • Allen N.B.
        • Fornito A.
        • Yücel M.
        Structural brain abnormalities in major depressive disorder: A selective review of recent MRI studies.
        J Affect Disord. 2009; 117: 1-17
        • Pizzagalli D.A.
        • Holmes A.J.
        • Dillon D.G.
        • Goetz E.L.
        • Birk J.L.
        • Bogdan R.
        • et al.
        Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder.
        Am J Psychiatry. 2009; 166: 702-710
        • Golden S.A.
        • Christoffel D.J.
        • Heshmati M.
        • Hodes G.E.
        • Magida J.
        • Davis K.
        • et al.
        Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression.
        Nat Med. 2013; 19: 337-344