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Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior

Published:December 28, 2017DOI:https://doi.org/10.1016/j.biopsych.2017.11.036

      Abstract

      Background

      Endocannabinoid signaling plays an important role in regulating synaptic transmission in the striatum, a brain region implicated as a central node of dysfunction in autism spectrum disorder. Deficits in signaling mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG) have been reported in mouse models of autism spectrum disorder, but a causal role for striatal 2-AG deficiency in phenotypes relevant to autism spectrum disorder has not been explored.

      Methods

      Using conditional knockout mice, we examined the electrophysiological, biochemical, and behavioral effects of 2-AG deficiency by deleting its primary synthetic enzyme, diacylglycerol lipase α (DGLα), from dopamine D1 receptor–expressing or adenosine A2a receptor–expressing medium spiny neurons (MSNs) to determine the role of 2-AG signaling in striatal direct or indirect pathways, respectively. We then used viral-mediated deletion of DGLα to study the effects of 2-AG deficiency in the ventral and dorsal striatum.

      Results

      Targeted deletion of DGLα from direct-pathway MSNs caused deficits in social interaction, excessive grooming, and decreased exploration of a novel environment. In contrast, deletion from indirect-pathway MSNs had no effect on any measure of behavior examined. Loss of 2-AG in direct-pathway MSNs also led to increased glutamatergic drive, which is consistent with a loss of retrograde feedback inhibition. Subregional DGLα deletion from the dorsal striatum produced deficits in social interaction, whereas deletion from the ventral striatum resulted in repetitive grooming.

      Conclusions

      These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and they demonstrate a key role for 2-AG in regulating striatal direct-pathway MSNs.

      Keywords

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      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders, 5th ed.
        American Psychiatric Association, Washington, DC2013
        • 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
        • Peñagarikano O.
        • Abrahams B.S.
        • Herman E.I.
        • Winden K.D.
        • Gdalyahu A.
        • Dong H.
        • et al.
        Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.
        Cell. 2011; 147: 235-246
        • Gunaydin L.A.
        • Grosenick L.
        • Finkelstein J.C.
        • Kauvar I.V.
        • Fenno L.E.
        • Adhikari A.
        • et al.
        Natural neural projection dynamics underlying social behavior.
        Cell. 2014; 157: 1535-1551
        • Di Martino A.
        • Kelly C.
        • Grzadzinski R.
        • Zuo X.N.
        • Mennes M.
        • Mairena M.A.
        • et al.
        Aberrant striatal functional connectivity in children with autism.
        Biol Psychiatry. 2011; 69: 847-856
        • Delmonte
        • Gallagher
        • O'Hanlon
        • McGrath
        • Balsters
        Functional and structural connectivity of frontostriatal circuitry in Autism Spectrum Disorder.
        Front Hum Neurosci. 2013; 7: 430
        • Hollander E.
        • Anagnostou E.
        • Chaplin W.
        • Esposito K.
        • Haznedar M.M.
        • Licalzi E.
        • et al.
        Striatal volume on magnetic resonance imaging and repetitive behaviors in autism.
        Biol Psychiatry. 2005; 58: 226-232
        • Wei D.
        • Lee D.
        • Cox C.D.
        • Karsten C.A.
        • Peñagarikano O.
        • Geschwind D.H.
        • Gall C.M.
        • Piomelli D.
        • et al.
        Endocannabinoid signaling mediates oxytocin-driven social reward.
        Proc Natl Acad Sci U S A. 2015; 112: 14084-14089
        • Karhson D.S.
        • Hardan A.Y.
        • Parker K.J.
        Endocannabinoid signaling in social functioning: an RDoC perspective.
        Transl Psychiatry. 2016; 6: e905
        • Manduca A.
        • Servadio M.
        • Damsteegt R.
        • Campolongo P.
        • Vanderschuren L.J.
        • Trezza V.
        Dopaminergic neurotransmission in the nucleus accumbens modulates social play behavior in rats.
        Neuropsychopharmacology. 2016; 41: 2215-2223
        • Chen M.
        • Wan Y.
        • Ade K.
        • Ting J.
        • Feng G.
        • Calakos N.
        Sapap3 deletion anomalously activates short-term endocannabinoid-mediated synaptic plasticity.
        J Neurosci. 2011; 31: 9563-9573
        • Gremel C.M.
        • Chancey J.H.
        • Atwood B.K.
        • Luo G.
        • Neve R.
        • Ramakrishnan C.
        • et al.
        Endocannabinoid modulation of orbitostriatal circuits gates habit formation.
        Neuron. 2016; 90: 1312-1324
        • Shonesy B.C.
        • Wang X.
        • Rose K.L.
        • Ramikie T.S.
        • Cavener V.S.
        • Rentz T.
        • et al.
        CaMKII regulates diacylglycerol lipase-α and striatal endocannabinoid signaling.
        Nat Neurosci. 2013; 16: 456-463
        • Uchigashima M.
        • Narushima M.
        • Fukaya M.
        • Katona I.
        • Kano M.
        • Watanabe M.
        Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum.
        J Neurosci. 2007; 27: 3663-3676
        • Kano M.
        • Ohno-Shosaku T.
        • Hashimotodani Y.
        • Uchigashima M.
        • Watanabe M.
        Endocannabinoid-mediated control of synaptic transmission.
        Physiol Rev. 2009; 89: 309-380
        • Anderson G.R.
        • Aoto J.
        • Tabuchi K.
        • Földy C.
        • Covy J.
        • Yee A.X.
        • et al.
        β-Neurexins control neural circuits by regulating synaptic endocannabinoid signaling.
        Cell. 2015; 162: 593-606
        • Doenni V.M.
        • Gray J.M.
        • Song C.M.
        • Patel S.
        • Hill M.N.
        • Pittman Q.J.
        Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling.
        Brain Behav Immun. 2016; 58: 237-247
        • Földy C.
        • Malenka R.C.
        • Südhof T.C.
        Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.
        Neuron. 2013; 78: 498-509
        • Kerr D.M.
        • Downey L.
        • Conboy M.
        • Finn D.P.
        • Roche M.
        Alterations in the endocannabinoid system in the rat valproic acid model of autism.
        Behav Brain Res. 2013; 249: 124-132
        • Rothwell P.E.
        • Fuccillo M.V.
        • Maxeiner S.
        • Hayton S.J.
        • Gokce O.
        • Lim B.K.
        • et al.
        Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors.
        Cell. 2014; 158: 198-212
        • Speed H.E.
        • Masiulis I.
        • Gibson J.R.
        • Powell C.M.
        Increased cortical inhibition in autism-linked neuroligin-3R451C mice is due in part to loss of endocannabinoid signaling.
        PLoS One. 2015; 10e0140638
        • Maccarrone M.
        • Rossi S.
        • Bari M.
        • De Chiara V.
        • Rapino C.
        • Musella A.
        • et al.
        Abnormal mGlu 5 receptor/endocannabinoid coupling in mice lacking FMRP and BC1 RNA.
        Neuropsychopharmacology. 2010; 35: 1500-1509
        • Shonesy B.C.
        • Bluett R.J.
        • Ramikie T.S.
        • Báldi R.
        • Hermanson D.J.
        • Kingsley P.J.
        • et al.
        Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation.
        Cell Rep. 2014; 9: 1644-1653
        • Tanimura A.
        • Yamazaki M.
        • Hashimotodani Y.
        • Uchigashima M.
        • Kawata S.
        • Abe M.
        • et al.
        The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission.
        Neuron. 2010; 65: 320-327
        • Gao Y.
        • Vasilyev D.V.
        • Goncalves M.B.
        • Howell F.V.
        • Hobbs C.
        • Reisenberg M.
        • et al.
        Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice.
        J Neurosci. 2010; 30: 2017-2024
        • Prasad A.
        • Merico D.
        • Thiruvahindrapuram B.
        • Wei J.
        • Lionel A.C.
        • Sato D.
        • et al.
        A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
        G3 (Bethesda). 2012; 2: 1665-1685
        • Miller D.T.
        • Adam M.P.
        • Aradhya S.
        • Biesecker L.G.
        • Brothman A.R.
        • Carter N.P.
        • et al.
        Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies.
        Am J Hum Genet. 2010; 86: 749-764
        • Kelleher 3rd, R.J.
        • Geigenmüller U.
        • Hovhannisyan H.
        • Trautman E.
        • Pinard R.
        • Rathmell B.
        • et al.
        High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.
        PLoS One. 2012; 7e35003
        • Fatemi S.H.
        • Folsom T.D.
        • Kneeland R.E.
        • Yousefi M.K.
        • Liesch S.B.
        • Thuras P.D.
        Impairment of fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling and its downstream cognates ras-related C3 botulinum toxin substrate 1, amyloid beta A4 precursor protein, striatal-enriched protein tyrosine phosphatase, and homer 1, in autism: a postmortem study in cerebellar vermis and superior frontal cortex.
        Mol Autism. 2013; 4: 21
        • Berkel S.
        • Marshall C.R.
        • Weiss B.
        • Howe J.
        • Roeth R.
        • Moog U.
        • et al.
        Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.
        Nat Genet. 2010; 42: 489-491
        • Durand C.M.
        • Betancur C.
        • Boeckers T.M.
        • Bockmann J.
        • Chaste P.
        • Fauchereau F.
        • et al.
        Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.
        Nat Genet. 2007; 39: 25-27
        • Gauthier J.
        • Spiegelman D.
        • Piton A.
        • Lafrenière R.G.
        • Laurent S.
        • St-Onge J.
        • et al.
        Novel de novo SHANK3 mutation in autistic patients.
        Am J Med Genet B Neuropsychiatr Genet. 2009; 150B: 421-424
        • Moessner R.
        • Marshall C.R.
        • Sutcliffe J.S.
        • Skaug J.
        • Pinto D.
        • Vincent J.
        • et al.
        Contribution of SHANK3 mutations to autism spectrum disorder.
        Am J Hum Genet. 2007; 81: 1289-1297
        • Stephenson J.R.
        • Wang X.
        • Perfitt T.L.
        • Parrish W.P.
        • Shonesy B.C.
        • Marks C.R.
        • et al.
        A novel human CAMK2A mutation disrupts dendritic morphology and synaptic transmission, and causes ASD-related behaviors.
        J Neurosci. 2017; 37: 2216-2233
        • Ninan I.
        Oxytocin suppresses basal glutamatergic transmission but facilitates activity-dependent synaptic potentiation in the medial prefrontal cortex.
        J Neurochem. 2011; 119: 324-331
        • Ghaleiha A.
        • Asadabadi M.
        • Mohammadi M.R.
        • Shahei M.
        • Tabrizi M.
        • Hajiaghaee R.
        • et al.
        Memantine as adjunctive treatment to risperidone in children with autistic disorder: A randomized, double-blind, placebo-controlled trial.
        Int J Neuropsychopharmacol. 2013; 16: 783-789
        • Bejjani A.
        • O'Neill J.
        • Kim J.A.
        • Frew A.J.
        • Yee V.W.
        • Ly R.
        • et al.
        Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI.
        PLoS One. 2012; 7e38786
        • Bluett R.J.
        • Báldi R.
        • Haymer A.
        • Gaulden A.D.
        • Hartley N.D.
        • Parrish W.P.
        • et al.
        Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.
        Nat Commun. 2017; 8: 14782
        • Gustin R.M.
        • Shonesy B.C.
        • Robinson S.L.
        • Rentz T.J.
        • Baucum 2nd, A.J.
        • Jalan-Sakrikar N.
        • et al.
        Loss of Thr286 phosphorylation disrupts synaptic CaMKIIα targeting, NMDAR activity and behavior in pre-adolescent mice.
        Mol Cell Neurosci. 2011; 47: 286-292
        • Ade K.K.
        • Wan Y.
        • Chen M.
        • Gloss B.
        • Calakos N.
        An improved BAC transgenic fluorescent reporter line for sensitive and specific identification of striatonigral medium spiny neurons.
        Front Syst Neurosci. 2011; 5: 32
        • Moy S.S.
        • Nadler J.J.
        • Young N.B.
        • Perez A.
        • Holloway L.P.
        • Barbaro R.P.
        • et al.
        Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains.
        Behav Brain Res. 2007; 176: 4-20
        • Welch J.M.
        • Lu J.
        • Rodriguiz R.M.
        • Trotta N.C.
        • Peca J.
        • Ding J.D.
        • et al.
        Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice.
        Nature. 2007; 448: 894-900
        • Hashimotodani Y.
        • Ohno-Shosaku T.
        • Tsubokawa H.
        • Ogata H.
        • Emoto K.
        • Maejima T.
        • et al.
        Phospholipase Cβ serves as a coincidence detector through its Ca2+ dependency for triggering retrograde endocannabinoid signal.
        Neuron. 2005; 45: 257-268
        • Shonesy B.C.
        • Winder D.G.
        • Patel S.
        • Colbran R.J.
        The initiation of synaptic 2-AG mobilization requires both an increased supply of diacylglycerol precursor and increased postsynaptic calcium.
        Neuropharmacology. 2015; 91: 57-62
        • Ledent C.
        • Valverde O.
        • Cossu G.
        • Petitet F.
        • Aubert J.F.
        • Beslot F.
        • et al.
        Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice.
        Science. 1999; 283: 401-404
        • Zimmer A.
        • Zimmer A.M.
        • Hohmann A.G.
        • Herkenham M.
        • Bonner T.I.
        Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice.
        Proc Natl Acad Sci U S A. 1999; 96: 5780-5785
        • Long J.Z.
        • Li W.
        • Booker L.
        • Burston J.J.
        • Kinsey S.G.
        • Schlosburg J.E.
        • et al.
        Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.
        Nat Chem Biol. 2009; 5: 37-44
        • Crombag H.S.
        • Johnson A.W.
        • Zimmer A.M.
        • Zimmer A.
        • Holland P.C.
        Deficits in sensory-specific devaluation task performance following genetic deletions of cannabinoid (CB1) receptor.
        Learn Mem. 2010; 17: 18-22
        • Hilário M.R.
        • Clouse E.
        • Yin H.H.
        • Costa R.M.
        Endocannabinoid signaling is critical for habit formation.
        Front Integr Neurosci. 2007; 1: 6
        • Marinho E.A.
        • Oliveira-Lima A.J.
        • Santos R.
        • Hollais A.W.
        • Baldaia M.A.
        • Wuo-Silva R.
        • et al.
        Effects of rimonabant on the development of single dose-induced behavioral sensitization to ethanol, morphine and cocaine in mice.
        Prog Neuropsychopharmacol Biol Psychiatry. 2015; 58: 22-31
        • Shen W.
        • Flajolet M.
        • Greengard P.
        • Surmeier D.J.
        Dichotomous dopaminergic control of striatal synaptic plasticity.
        Science. 2008; 321: 848-851
        • Kreitzer A.C.
        • Malenka R.C.
        Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models.
        Nature. 2007; 445: 643-647
        • Lerner T.N.
        • Kreitzer A.C.
        RGS4 is required for dopaminergic control of striatal LTD and susceptibility to Parkinsonian motor deficits.
        Neuron. 2012; 73: 347-359
        • Balleine B.W.
        • O'Doherty J.P.
        Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action.
        Neuropsychopharmacology. 2010; 35: 48-69
        • Graybiel A.M.
        Habits, rituals, and the evaluative brain.
        Annu Rev Neurosci. 2008; 31: 359-387
        • Yin H.H.
        • Knowlton B.J.
        • Balleine B.W.
        Inactivation of dorsolateral striatum enhances sensitivity to changes in the action-outcome contingency in instrumental conditioning.
        Behav Brain Res. 2006; 166: 189-196
        • Ade K.K.
        • Wan Y.
        • Hamann H.C.
        • O'Hare J.K.
        • Guo W.
        • Quian A.
        • et al.
        Increased metabotropic glutamate receptor 5 signaling underlies obsessive-compulsive disorder-like behavioral and striatal circuit abnormalities in mice.
        Biol Psychiatry. 2016; 80: 522-533
        • Wang W.
        • Li C.
        • Chen Q.
        • van der Goes M.S.
        • Hawrot J.
        • Yao A.Y.
        • et al.
        Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism.
        J Clin Invest. 2017; 127: 1978-1990