Advertisement

Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32–Dependent D1 Dopamine Receptor Signaling and Behaviors

      Abstract

      Background

      The serine-threonine kinase mTORC1 (mechanistic target of rapamycin complex 1) is essential for normal cell function but is aberrantly activated in the brain in both genetic-developmental and sporadic diseases and is associated with a spectrum of neuropsychiatric symptoms. The underlying molecular mechanisms of cognitive and neuropsychiatric symptoms remain controversial.

      Methods

      The present study examines behaviors in transgenic models that express Rheb, the most proximal known activator of mTORC1, and profiles striatal phosphoproteomics in a model with persistently elevated mTORC1 signaling. Biochemistry, immunohistochemistry, electrophysiology, and behavior approaches are used to examine the impact of persistently elevated mTORC1 on D1 dopamine receptor (D1R) signaling. The effect of persistently elevated mTORC1 was confirmed using D1-Cre to elevate mTORC1 activity in D1R neurons.

      Results

      We report that persistently elevated mTORC1 signaling blocks canonical D1R signaling that is dependent on DARPP-32 (dopamine- and cAMP-regulated neuronal phosphoprotein). The immediate downstream effector of mTORC1, ribosomal S6 kinase 1 (S6K1), phosphorylates and activates DARPP-32. Persistent elevation of mTORC1-S6K1 occludes dynamic D1R signaling downstream of DARPP-32 and blocks multiple D1R responses, including dynamic gene expression, D1R-dependent corticostriatal plasticity, and D1R behavioral responses including sociability. Candidate biomarkers of mTORC1–DARPP-32 occlusion are increased in the brain of human disease subjects in association with elevated mTORC1-S6K1, supporting a role for this mechanism in cognitive disease.

      Conclusions

      The mTORC1-S6K1 intersection with D1R signaling provides a molecular framework to understand the effects of pathological mTORC1 activation on behavioral symptoms in neuropsychiatric disease.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Saxton R.A.
        • Sabatini D.M.
        mTOR signaling in growth, metabolism, and disease.
        Cell. 2017; 168: 960-976
        • Lipton Jonathan O.
        • Sahin M.
        The neurology of mTOR.
        Neuron. 2014; 84: 275-291
        • Costa-Mattioli M.
        • Monteggia L.M.
        mTOR complexes in neurodevelopmental and neuropsychiatric disorders.
        Nat Neurosci. 2013; 16: 1537-1543
        • Curatolo P.
        • Moavero R.
        • de Vries P.J.
        Neurological and neuropsychiatric aspects of tuberous sclerosis complex.
        Lancet Neurol. 2015; 14: 733-745
        • Butler M.G.
        • Dasouki M.J.
        • Zhou X.-P.
        • Talebizadeh Z.
        • Brown M.
        • Takahashi T.N.
        • et al.
        Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.
        J Med Genet. 2005; 42: 318-321
        • An W.-L.
        • Cowburn R.F.
        • Li L.
        • Braak H.
        • Alafuzoff I.
        • Iqbal K.
        • et al.
        Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer’s disease.
        Am J Pathol. 2003; 163: 591-607
        • Nixon R.A.
        The role of autophagy in neurodegenerative disease.
        Nat Med. 2013; 19: 983-997
        • Howell K.R.
        • Law A.J.
        Neurodevelopmental concepts of schizophrenia in the genome-wide association era: AKT/mTOR signaling as a pathological mediator of genetic and environmental programming during development.
        Schizophr Res. 2019; 217: 95-104
        • Tsai P.T.
        • Hull C.
        • Chu Y.
        • Greene-Colozzi E.
        • Sadowski A.R.
        • Leech J.M.
        • et al.
        Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.
        Nature. 2012; 488: 647-651
        • Ehninger D.
        • Han S.
        • Shilyansky C.
        • Zhou Y.
        • Li W.
        • Kwiatkowski D.J.
        • et al.
        Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis.
        Nat Med. 2008; 14: 843-848
        • Zhou J.
        • Blundell J.
        • Ogawa S.
        • Kwon C.-H.
        • Zhang W.
        • Sinton C.
        • et al.
        Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice.
        J Neurosci. 2009; 29: 1773-1783
        • Auerbach B.D.
        • Osterweil E.K.
        • Bear M.F.
        Mutations causing syndromic autism define an axis of synaptic pathophysiology.
        Nature. 2011; 480: 63-68
        • Gkogkas C.G.
        • Khoutorsky A.
        • Ran I.
        • Rampakakis E.
        • Nevarko T.
        • Weatherill D.B.
        • et al.
        Autism-related deficits via dysregulated eIF4E-dependent translational control.
        Nature. 2012; 493: 371-377
        • Santini E.
        • Huynh T.N.
        • MacAskill A.F.
        • Carter A.G.
        • Pierre P.
        • Ruggero D.
        • et al.
        Exaggerated translation causes synaptic and behavioural aberrations associated with autism.
        Nature. 2012; 493: 411-415
        • Michalon A.
        • Sidorov M.
        • Ballard Theresa M.
        • Ozmen L.
        • Spooren W.
        • Wettstein Joseph G.
        • et al.
        Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice.
        Neuron. 2012; 74: 49-56
        • Chen C.-J.
        • Sgritta M.
        • Mays J.
        • Zhou H.
        • Lucero R.
        • Park J.
        • et al.
        Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency.
        Nat Med. 2019; 25: 1684-1690
        • Xu Z.-X.
        • Kim G.H.
        • Tan J.-W.
        • Riso A.E.
        • Sun Y.
        • Xu E.Y.
        • et al.
        Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations.
        Nat Commun. 2020; 11: 1797
        • Zhu P.J.
        • Chen C.-J.
        • Mays J.
        • Stoica L.
        • Costa-Mattioli M.
        mTORC2, but not mTORC1, is required for hippocampal mGluR-LTD and associated behaviors.
        Nat Neurosci. 2018; 21: 799-802
        • Yang H.
        • Jiang X.
        • Li B.
        • Yang H.J.
        • Miller M.
        • Yang A.
        • et al.
        Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.
        Nature. 2017; 552: 368-373
        • Yan L.
        • Findlay G.M.
        • Jones R.
        • Procter J.
        • Cao Y.
        • Lamb R.F.
        Hyperactivation of mammalian target of rapamycin (mTOR) signaling by a gain-of-function mutant of the Rheb GTPase.
        J Biol Chem. 2006; 281: 19793-19797
        • Zou J.
        • Zhou L.
        • Du X.-X.
        • Ji Y.
        • Xu J.
        • Tian J.
        • et al.
        Rheb1 is required for mTORC1 and myelination in postnatal brain development.
        Dev Cell. 2011; 20: 97-108
        • Gunaydin Lisa A.
        • Grosenick L.
        • Finkelstein Joel C.
        • Kauvar Isaac V.
        • Fenno Lief E.
        • Adhikari A.
        • et al.
        Natural neural projection dynamics underlying social behavior.
        Cell. 2014; 157: 1535-1551
        • Dölen G.
        • Darvishzadeh A.
        • Huang K.W.
        • Malenka R.C.
        Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin.
        Nature. 2013; 501: 179-184
        • Hsu P.P.
        • Kang S.A.
        • Rameseder J.
        • Zhang Y.
        • Ottina K.A.
        • Lim D.
        • et al.
        The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling.
        Science. 2011; 332: 1317-1322
        • Pearce L.R.
        • Komander D.
        • Alessi D.R.
        The nuts and bolts of AGC protein kinases.
        Nat Rev Mol Cell Biol. 2010; 11: 9-22
        • Beaulieu J.-M.
        • Gainetdinov R.R.
        The physiology, signaling, and pharmacology of dopamine receptors.
        Pharmacol Rev. 2011; 63: 182-217
        • Nagai T.
        • Nakamuta S.
        • Kuroda K.
        • Nakauchi S.
        • Nishioka T.
        • Takano T.
        • et al.
        Phosphoproteomics of the dopamine pathway enables discovery of Rap1 activation as a reward signal in vivo.
        Neuron. 2016; 89: 550-565
        • Bateup H.S.
        • Svenningsson P.
        • Kuroiwa M.
        • Gong S.
        • Nishi A.
        • Heintz N.
        • et al.
        Cell type–specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs.
        Nat Neurosci. 2008; 11: 932-939
        • 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
        • Valjent E.
        • Pascoli V.
        • Svenningsson P.
        • Paul S.
        • Enslen H.
        • Corvol J.-C.
        • et al.
        Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum.
        Proc Natl Acad Sci U S A. 2005; 102: 491-496
        • Ahn J.-H.
        • McAvoy T.
        • Rakhilin S.V.
        • Nishi A.
        • Greengard P.
        • Nairn A.C.
        Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56δ subunit.
        Proc Natl Acad Sci U S A. 2007; 104: 2979-2984
        • Stipanovich A.
        • Valjent E.
        • Matamales M.
        • Nishi A.
        • Ahn J.-H.
        • Maroteaux M.
        • et al.
        A phosphatase cascade by which rewarding stimuli control nucleosomal response.
        Nature. 2008; 453: 879-884
        • Huynh T.N.
        • Santini E.
        • Klann E.
        Requirement of mammalian target of rapamycin complex 1 downstream effectors in cued fear memory reconsolidation and its persistence.
        J Neurosci. 2014; 34: 9034-9039
        • Park Joo M.
        • Hu J.-H.
        • Milshteyn A.
        • Zhang P.-W.
        • Moore Chester G.
        • Park S.
        • et al.
        A prolyl-isomerase mediates dopamine-dependent plasticity and cocaine motor sensitization.
        Cell. 2013; 154: 637-650
        • Centonze D.
        • Costa C.
        • Rossi S.
        • Prosperetti C.
        • Pisani A.
        • Usiello A.
        • et al.
        Chronic cocaine prevents depotentiation at corticostriatal synapses.
        Biol Psychiatry. 2006; 60: 436-443
        • Lim B.K.
        • Huang K.W.
        • Grueter B.A.
        • Rothwell P.E.
        • Malenka R.C.
        Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens.
        Nature. 2012; 487: 183-189
        • Francis T.C.
        • Gaynor A.
        • Chandra R.
        • Fox M.E.
        • Lobo M.K.
        The selective RhoA inhibitor rhosin promotes stress resiliency through enhancing D1-medium spiny neuron plasticity and reducing hyperexcitability.
        Biol Psychiatry. 2019; 85: 1001-1010
        • Lee Y.
        • Kim H.
        • Kim J.E.
        • Park J.Y.
        • Choi J.
        • Lee J.E.
        • et al.
        Excessive D1 dopamine receptor activation in the dorsal striatum promotes autistic-like behaviors.
        Mol Neurobiol. 2018; 55: 5658-5671
        • Peça J.
        • Feliciano C.
        • Ting J.T.
        • Wang W.
        • Wells M.F.
        • Venkatraman T.N.
        • et al.
        Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.
        Nature. 2011; 472: 437-442
        • Zhang J.
        • Zhang L.
        • Jiao H.
        • Zhang Q.
        • Zhang D.
        • Lou D.
        • et al.
        c-Fos facilitates the acquisition and extinction of cocaine-induced persistent changes.
        J Neurosci. 2006; 26: 13287-13296
        • Brozoski T.
        • Brown R.
        • Rosvold H.
        • Goldman P.
        Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey.
        Science. 1979; 205: 929-932
        • Sawaguchi T.
        • Goldman-Rakic P.
        D1 dopamine receptors in prefrontal cortex: Involvement in working memory.
        Science. 1991; 251: 947-950
        • Kosillo P.
        • Doig N.M.
        • Ahmed K.M.
        • Agopyan-Miu A.H.C.W.
        • Wong C.D.
        • Conyers L.
        • et al.
        Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility.
        Nat Commun. 2019; 10: 5426
        • Choi C.H.
        • Schoenfeld B.P.
        • Bell A.J.
        • Hinchey J.
        • Rosenfelt C.
        • Gertner M.J.
        • et al.
        Multiple drug treatments that increase cAMP signaling restore long-term memory and aberrant signaling in fragile X syndrome models.
        Front Behav Neurosci. 2016; 10: 136
        • Chiang A.C.A.
        • Fowler S.W.
        • Savjani R.R.
        • Hilsenbeck S.G.
        • Wallace C.E.
        • Cirrito J.R.
        • et al.
        Combination anti-Aβ treatment maximizes cognitive recovery and rebalances mTOR signaling in APP mice.
        J Exp Med. 2018; 215: 1349-1364
        • Wolinsky D.
        • Drake K.
        • Bostwick J.
        Diagnosis and management of neuropsychiatric symptoms in Alzheimer’s disease.
        Curr Psychiatry Rep. 2018; 20: 117
        • LeGates T.A.
        • Kvarta M.D.
        • Tooley J.R.
        • Francis T.C.
        • Lobo M.K.
        • Creed M.C.
        • et al.
        Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses.
        Nature. 2018; 564: 258-262
        • Francis T.C.
        • Chandra R.
        • Friend D.M.
        • Finkel E.
        • Dayrit G.
        • Miranda J.
        • et al.
        Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress.
        Biol Psychiatry. 2015; 77: 212-222
        • Francis T.C.
        • Chandra R.
        • Gaynor A.
        • Konkalmatt P.
        • Metzbower S.R.
        • Evans B.
        • et al.
        Molecular basis of dendritic atrophy and activity in stress susceptibility.
        Mol Psychiatry. 2017; 22: 1512-1519
        • Krishnan V.
        • Han M.H.
        • Graham D.L.
        • Berton O.
        • Renthal W.
        • Russo S.J.
        • et al.
        Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.
        Cell. 2007; 131: 391-404
        • Berton O.
        • McClung C.A.
        • Dileone R.J.
        • Krishnan V.
        • Renthal W.
        • Russo S.J.
        • et al.
        Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
        Science. 2006; 311: 864-868
        • Ruisoto P.
        • Contador I.
        The role of stress in drug addiction: An integrative review.
        Physiol Behav. 2019; 202: 62-68
        • Sonnenschein S.F.
        • Gomes F.V.
        • Grace A.A.
        Dysregulation of midbrain dopamine system and the pathophysiology of schizophrenia.
        Front Psychiatry. 2020; 11: 613
        • Snyder G.
        • Girault J.
        • Chen J.
        • Czernik A.
        • Kebabian J.
        • Nathanson J.
        • et al.
        Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: Regulation by factors other than dopamine.
        J Neurosci. 1992; 12: 3071-3083
        • Holz M.K.
        • Ballif B.A.
        • Gygi S.P.
        • Blenis J.
        mTOR and S6K1 Mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.
        Cell. 2005; 123: 569-580
        • Sawicka K.
        • Pyronneau A.
        • Chao M.
        • Bennett M.V.L.
        • Zukin R.S.
        Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice.
        Proc Natl Acad Sci U S A. 2016; 113: E6290-E6297
        • Chévere-Torres I.
        • Kaphzan H.
        • Bhattacharya A.
        • Kang A.
        • Maki J.M.
        • Gambello M.J.
        • et al.
        Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the ΔRG mouse model of tuberous sclerosis complex.
        Neurobiol Dis. 2012; 45: 1101-1110

      Linked Article

      • The Convergence of Two Signaling Pathways Within the Striatum Reveals Potential Mechanisms of Neuropsychiatric Disease
        Biological PsychiatryVol. 89Issue 11
        • Preview
          The serine-threonine kinase mTOR (mechanistic target of rapamycin) is the cornerstone of a signaling pathway that serves as an essential regulator of cellular processes such as protein synthesis and autophagy (1). Aberrant activity of mTOR complex 1 (mTORC1) has been identified both in neurodevelopmental disorders and in sporadic neurodegenerative disease (2). In particular, loss-of-function mutations in genes encoding negative regulators of mTORC1, such as TSC1, TSC2, and PTEN, result in syndromic neurodevelopmental disorders associated with a constellation of manifestations, which can include epilepsy, autism spectrum disorder, and cognitive impairments.
        • Full-Text
        • PDF