Metabotropic Glutamate Receptor 5 in Amygdala Target Neurons Regulates Susceptibility to Chronic Social Stress

  • Author Footnotes
    1 JK and SK contributed equally to this work.
    Jeongseop Kim
    1 JK and SK contributed equally to this work.
    Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu, Republic of Korea

    Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
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  • Author Footnotes
    1 JK and SK contributed equally to this work.
    Shinwoo Kang
    1 JK and SK contributed equally to this work.
    Department of Pharmacology, College of Medicine, Gachon University, Incheon, Republic of Korea

    Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea

    Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea

    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
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  • Tae-Yong Choi
    Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu, Republic of Korea
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  • Author Footnotes
    2 K-AC and JWK contributed equally to this work.
    Keun-A Chang
    Address correspondence to Keun-A Chang, Ph.D.
    2 K-AC and JWK contributed equally to this work.
    Department of Pharmacology, College of Medicine, Gachon University, Incheon, Republic of Korea

    Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea

    Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea
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  • Author Footnotes
    2 K-AC and JWK contributed equally to this work.
    Ja Wook Koo
    Ja Wook Koo, Ph.D.
    2 K-AC and JWK contributed equally to this work.
    Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu, Republic of Korea

    Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
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  • Author Footnotes
    1 JK and SK contributed equally to this work.
    2 K-AC and JWK contributed equally to this work.



      Metabotropic glutamate receptor 5 (mGluR5) has been implicated in stress-related psychiatric disorders, particularly major depressive disorder. Although growing evidence supports the proresilient role of mGluR5 in corticolimbic circuitry in the depressive-like behaviors following chronic stress exposure, the underlying neural mechanisms, including circuits and molecules, remain unknown.


      We measured the c-Fos expression and probability of neurotransmitter release in and from basolateral amygdala (BLA) neurons projecting to the medial prefrontal cortex (mPFC) and to the ventral hippocampus (vHPC) after chronic social defeat stress. The role of BLA projections in depressive-like behaviors was assessed using optogenetic manipulations, and the underlying molecular mechanisms of mGluR5 and downstream signaling were investigated by Western blotting, viral-mediated gene transfer, and pharmacological manipulations.


      Chronic social defeat stress disrupted neural activity and glutamatergic transmission in both BLA projections. Optogenetic activation of BLA projections reversed the detrimental effects of chronic social defeat stress on depressive-like behaviors and mGluR5 expression in the mPFC and vHPC. Conversely, inhibition of BLA projections of mice undergoing subthreshold social defeat stress induced a susceptible phenotype and mGluR5 reduction. These two BLA circuits appeared to act in an independent way. We demonstrate that mGluR5 overexpression in the mPFC or vHPC was proresilient while the mGluR5 knockdown was prosusceptible and that the proresilient effects of mGluR5 are mediated through distinctive downstream signaling pathways in the mPFC and vHPC.


      These findings identify mGluR5 in the mPFC and vHPC that receive BLA inputs as a critical mediator of stress resilience, highlighting circuit-specific signaling for depressive-like behaviors.


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        • GBD 2017 Disease and Injury Incidence and Prevalence Collaborators
        Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017 [published correction appears in Lancet 2019; 393:e44].
        Lancet. 2018; 392: 1789-1858
        • Kessler R.C.
        The effects of stressful life events on depression.
        Annu Rev Psychol. 1997; 48: 191-214
        • Kendler K.S.
        • Karkowski L.M.
        • Prescott C.A.
        Causal relationship between stressful life events and the onset of major depression.
        Am J Psychiatry. 1999; 156: 837-841
        • Feder A.
        • Nestler E.J.
        • Charney D.S.
        Psychobiology and molecular genetics of resilience.
        Nat Rev Neurosci. 2009; 10: 446-457
        • Han M.H.
        • Nestler E.J.
        Neural substrates of depression and resilience.
        Neurotherapeutics. 2017; 14: 677-686
        • Reus G.Z.
        • de Moura A.B.
        • Silva R.H.
        • Resende W.R.
        • Quevedo J.
        Resilience dysregulation in major depressive disorder: Focus on glutamatergic imbalance and microglial activation.
        Curr Neuropharmacol. 2018; 16: 297-307
        • McEwen B.S.
        • Gray J.
        • Nasca C.
        Recognizing resilience: Learning from the effects of stress on the brain.
        Neurobiol Stress. 2015; 1: 1-11
        • Zhang W.H.
        • Zhang J.Y.
        • Holmes A.
        • Pan B.X.
        Amygdala circuit substrates for stress adaptation and adversity.
        Biol Psychiatry. 2021; 89: 847-856
        • Tye K.M.
        Neural circuit motifs in valence processing.
        Neuron. 2018; 100: 436-452
        • O’Neill P.K.
        • Gore F.
        • Salzman C.D.
        Basolateral amygdala circuitry in positive and negative valence.
        Curr Opin Neurobiol. 2018; 49: 175-183
        • Felix-Ortiz A.C.
        • Tye K.M.
        Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior.
        J Neurosci. 2014; 34: 586-595
        • Liu W.Z.
        • Zhang W.H.
        • Zheng Z.H.
        • Zou J.X.
        • Liu X.X.
        • Huang S.H.
        • et al.
        Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety.
        Nat Commun. 2020; 11: 2221
        • Ma H.
        • Li C.
        • Wang J.
        • Zhang X.
        • Li M.
        • Zhang R.
        • et al.
        Amygdala-hippocampal innervation modulates stress-induced depressive-like behaviors through AMPA receptors.
        Proc Natl Acad Sci U S A. 2021; 118e2019409118
        • Yang Y.
        • Wang Z.H.
        • Jin S.
        • Gao D.
        • Liu N.
        • Chen S.P.
        • et al.
        Opposite monosynaptic scaling of BLP–vCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory.
        Nat Commun. 2016; 7: 11935
        • Burgos-Robles A.
        • Kimchi E.Y.
        • Izadmehr E.M.
        • Porzenheim M.J.
        • Ramos-Guasp W.A.
        • Nieh E.H.
        • et al.
        Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment.
        Nat Neurosci. 2017; 20: 824-835
        • Duman R.S.
        • Sanacora G.
        • Krystal J.H.
        Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments.
        Neuron. 2019; 102: 75-90
        • Lener M.S.
        • Niciu M.J.
        • Ballard E.D.
        • Park M.
        • Park L.T.
        • Nugent A.C.
        • Zarate Jr., C.A.
        Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine.
        Biol Psychiatry. 2017; 81: 886-897
        • Esterlis I.
        • Holmes S.E.
        • Sharma P.
        • Krystal J.H.
        • DeLorenzo C.
        Metabotropic glutamatergic receptor 5 and stress disorders: Knowledge gained from receptor imaging studies.
        Biol Psychiatry. 2018; 84: 95-105
        • Terbeck S.
        • Akkus F.
        • Chesterman L.P.
        • Hasler G.
        The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: Combining preclinical evidence with human positron emission tomography (PET) studies.
        Front Neurosci. 2015; 9: 86
        • Krystal J.H.
        • Mathew S.J.
        • D’Souza D.C.
        • Garakani A.
        • Gunduz-Bruce H.
        • Charney D.S.
        Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists.
        CNS Drugs. 2010; 24: 669-693
        • Abdallah C.G.
        • Hannestad J.
        • Mason G.F.
        • Holmes S.E.
        • DellaGioia N.
        • Sanacora G.
        • et al.
        Metabotropic glutamate receptor 5 and glutamate involvement in major depressive disorder: A multimodal imaging study.
        Biol Psychiatry Cogn Neurosci Neuroimaging. 2017; 2: 449-456
        • Kim J.H.
        • Joo Y.H.
        • Son Y.D.
        • Kim J.H.
        • Kim Y.K.
        • Kim H.K.
        • et al.
        In vivo metabotropic glutamate receptor 5 availability-associated functional connectivity alterations in drug-naïve young adults with major depression.
        Eur Neuropsychopharmacol. 2019; 29: 278-290
        • Deschwanden A.
        • Karolewicz B.
        • Feyissa A.M.
        • Treyer V.
        • Ametamey S.M.
        • Johayem A.
        • et al.
        Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study.
        Am J Psychiatry. 2011; 168: 727-734
        • Howard D.M.
        • Adams M.J.
        • Shirali M.
        • Clarke T.K.
        • Marioni R.E.
        • Davies G.
        • et al.
        Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways [published correction appears in Nat Commun 2021; 12:2012].
        Nat Commun. 2018; 9: 1470
        • Iyo A.H.
        • Feyissa A.M.
        • Chandran A.
        • Austin M.C.
        • Regunathan S.
        • Karolewicz B.
        Chronic corticosterone administration down-regulates metabotropic glutamate receptor 5 protein expression in the rat hippocampus.
        Neuroscience. 2010; 169: 1567-1574
        • Wierońska J.M.
        • Brański P.
        • Szewczyk B.
        • Pałucha A.
        • Papp M.
        • Gruca P.
        • et al.
        Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in the rat hippocampus in an animal model of depression.
        Pol J Pharmacol. 2001; 53: 659-662
        • Kovačević T.
        • Skelin I.
        • Minuzzi L.
        • Rosa-Neto P.
        • Diksic M.
        Reduced metabotropic glutamate receptor 5 in the Flinders Sensitive Line of rats, an animal model of depression: An autoradiographic study.
        Brain Res Bull. 2012; 87: 406-412
        • Shin S.
        • Kwon O.
        • Kang J.I.
        • Kwon S.
        • Oh S.
        • Choi J.
        • et al.
        mGluR5 in the nucleus accumbens is critical for promoting resilience to chronic stress.
        Nat Neurosci. 2015; 18: 1017-1024
        • Lee K.W.
        • Westin L.
        • Kim J.
        • Chang J.C.
        • Oh Y.S.
        • Amreen B.
        • et al.
        Alteration by p11 of mGluR5 localization regulates depression-like behaviors.
        Mol Psychiatry. 2015; 20: 1546-1556
        • 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
        • Krishnan V.
        • Nestler E.J.
        Animal models of depression: Molecular perspectives.
        Curr Top Behav Neurosci. 2011; 7: 121-147
        • Koo J.W.
        • Labonté B.
        • Engmann O.
        • Calipari E.S.
        • Juarez B.
        • Lorsch Z.
        • et al.
        Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress-induced depressive behaviors.
        Biol Psychiatry. 2016; 80: 469-478
        • Walsh J.J.
        • Friedman A.K.
        • Sun H.
        • Heller E.A.
        • Ku S.M.
        • Juarez B.
        • et al.
        Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway.
        Nat Neurosci. 2014; 17: 27-29
        • Chaudhury D.
        • Walsh J.J.
        • Friedman A.K.
        • Juarez B.
        • Ku S.M.
        • Koo J.W.
        • et al.
        Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.
        Nature. 2013; 493: 532-536
        • Barth A.L.
        • Gerkin R.C.
        • Dean K.L.
        Alteration of neuronal firing properties after in vivo experience in a FosGFP transgenic mouse.
        J Neurosci. 2004; 24: 6466-6475
        • Morgan J.I.
        • Cohen D.R.
        • Hempstead J.L.
        • Curran T.
        Mapping patterns of c-fos expression in the central nervous system after seizure.
        Science. 1987; 237: 192-197
        • Goldstein L.
        The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction.
        Yale J Biol Med. 1992; 65: 540-542
        • Liu J.
        • Hu T.
        • Zhang M.Q.
        • Xu C.Y.
        • Yuan M.Y.
        • Li R.X.
        Differential efferent projections of GABAergic neurons in the basolateral and central nucleus of amygdala in mice.
        Neurosci Lett. 2021; 745: 135621
        • Manabe T.
        • Wyllie D.J.
        • Perkel D.J.
        • Nicoll R.A.
        Modulation of synaptic transmission and long-term potentiation: Effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus.
        J Neurophysiol. 1993; 70: 1451-1459
        • Dobrunz L.E.
        • Stevens C.F.
        Heterogeneity of release probability, facilitation, and depletion at central synapses.
        Neuron. 1997; 18: 995-1008
        • Mao L.
        • Yang L.
        • Tang Q.
        • Samdani S.
        • Zhang G.
        • Wang J.Q.
        The scaffold protein Homer1b/c links metabotropic glutamate receptor 5 to extracellular signal-regulated protein kinase cascades in neurons.
        J Neurosci. 2005; 25: 2741-2752
        • Stoppel L.J.
        • Auerbach B.D.
        • Senter R.K.
        • Preza A.R.
        • Lefkowitz R.J.
        • Bear M.F.
        β-Arrestin2 couples metabotropic glutamate receptor 5 to neuronal protein synthesis and is a potential target to treat fragile X.
        Cell Rep. 2017; 18: 2807-2814
        • Olmo I.G.
        • Ferreira-Vieira T.H.
        • Ribeiro F.M.
        Dissecting the signaling pathways involved in the crosstalk between metabotropic glutamate 5 and cannabinoid type 1 receptors.
        Mol Pharmacol. 2016; 90: 609-619
        • Holz A.
        • Mülsch F.
        • Schwarz M.K.
        • Hollmann M.
        • Döbrössy M.D.
        • Coenen V.A.
        • et al.
        Enhanced mGlu5 signaling in excitatory neurons promotes rapid antidepressant effects via AMPA receptor activation.
        Neuron. 2019; 104: 338-352.e7
        • Tang Y.
        • Kong L.
        • Wu F.
        • Womer F.
        • Jiang W.
        • Cao Y.
        • et al.
        Decreased functional connectivity between the amygdala and the left ventral prefrontal cortex in treatment-naive patients with major depressive disorder: A resting-state functional magnetic resonance imaging study.
        Psychol Med. 2013; 43: 1921-1927
        • Cullen K.R.
        • Westlund M.K.
        • Klimes-Dougan B.
        • Mueller B.A.
        • Houri A.
        • Eberly L.E.
        • Lim K.O.
        Abnormal amygdala resting-state functional connectivity in adolescent depression [published correction appears in JAMA Psychiatry 2018; 75:104].
        JAMA Psychiatry. 2014; 71: 1138-1147
        • Ulrich-Lai Y.M.
        • Herman J.P.
        Neural regulation of endocrine and autonomic stress responses.
        Nat Rev Neurosci. 2009; 10: 397-409
        • Son H.
        • Baek J.H.
        • Go B.S.
        • Jung D.H.
        • Sontakke S.B.
        • Chung H.J.
        • et al.
        Glutamine has antidepressive effects through increments of glutamate and glutamine levels and glutamatergic activity in the medial prefrontal cortex.
        Neuropharmacology. 2018; 143: 143-152
        • McGarry L.M.
        • Carter A.G.
        Prefrontal cortex drives distinct projection neurons in the basolateral amygdala.
        Cell Rep. 2017; 21: 1426-1433
        • Hintiryan H.
        • Bowman I.
        • Johnson D.L.
        • Korobkova L.
        • Zhu M.
        • Khanjani N.
        • et al.
        Connectivity characterization of the mouse basolateral amygdalar complex.
        Nat Commun. 2021; 12: 2859
        • Beyeler A.
        • Chang C.J.
        • Silvestre M.
        • Lévêque C.
        • Namburi P.
        • Wildes C.P.
        • Tye K.M.
        Organization of valence-encoding and projection-defined neurons in the basolateral amygdala.
        Cell Rep. 2018; 22: 905-918
        • Pi G.
        • Gao D.
        • Wu D.
        • Wang Y.
        • Lei H.
        • Zeng W.
        • et al.
        Posterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect.
        Nat Commun. 2020; 11: 183
        • Bagot R.C.
        • Parise E.M.
        • Peña C.J.
        • Zhang H.X.
        • Maze I.
        • Chaudhury D.
        • et al.
        Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression [published correction appears in Nat Commun 2015; 6:7626].
        Nat Commun. 2015; 6: 7062
        • Nestler E.J.
        Role of the brain’s reward circuitry in depression: Transcriptional mechanisms.
        in: Nicotine Use in Mental Illness and Neurological Disorders. vol. 124.. Academic Press, Waltham, MA2015: 151-170
        • Dieterich A.
        • Floeder J.
        • Stech K.
        • Lee J.
        • Srivastava P.
        • Barker D.J.
        • Samuels B.A.
        Activation of basolateral amygdala to nucleus accumbens projection neurons attenuates chronic corticosterone-induced behavioral deficits in male mice.
        Front Behav Neurosci. 2021; 15: 643272
        • Muir J.
        • Lopez J.
        • Bagot R.C.
        Wiring the depressed brain: Optogenetic and chemogenetic circuit interrogation in animal models of depression.
        Neuropsychopharmacology. 2019; 44: 1013-1026
        • Knowland D.
        • Lim B.K.
        Circuit-based frameworks of depressive behaviors: The role of reward circuitry and beyond.
        Pharmacol Biochem Behav. 2018; 174: 42-52
        • Banasr M.
        • Chowdhury G.M.I.
        • Terwilliger R.
        • Newton S.S.
        • Duman R.S.
        • Behar K.L.
        • Sanacora G.
        Glial pathology in an animal model of depression: Reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole.
        Mol Psychiatry. 2010; 15: 501-511
        • Baek J.H.
        • Vignesh A.
        • Son H.
        • Lee D.H.
        • Roh G.S.
        • Kang S.S.
        • et al.
        Glutamine supplementation ameliorates chronic stress-induced reductions in glutamate and glutamine transporters in the mouse prefrontal cortex.
        Exp Neurobiol. 2019; 28: 270-278
        • Hasler G.
        • van der Veen J.W.
        • Tumonis T.
        • Meyers N.
        • Shen J.
        • Drevets W.C.
        Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy.
        Arch Gen Psychiatry. 2007; 64: 193-200
        • Block W.
        • Träber F.
        • von Widdern O.
        • Metten M.
        • Schild H.
        • Maier W.
        • et al.
        Proton MR spectroscopy of the hippocampus at 3 T in patients with unipolar major depressive disorder: Correlates and predictors of treatment response.
        Int J Neuropsychopharmacol. 2009; 12: 415-422
        • Wagner K.V.
        • Hartmann J.
        • Labermaier C.
        • Häusl A.S.
        • Zhao G.
        • Harbich D.
        • et al.
        Homer1/mGluR5 activity moderates vulnerability to chronic social stress.
        Neuropsychopharmacology. 2015; 40: 1222-1233
        • Li M.X.
        • Li Q.
        • Sun X.J.
        • Luo C.
        • Li Y.
        • Wang Y.N.
        • et al.
        Increased Homer1-mGluR5 mediates chronic stress-induced depressive-like behaviors and glutamatergic dysregulation via activation of PERK-eIF2α.
        Prog Neuropsychopharmacol Biol Psychiatry. 2019; 95: 109682
        • Fanselow M.S.
        • Dong H.W.
        Are the dorsal and ventral hippocampus functionally distinct structures?.
        Neuron. 2010; 65: 7-19
        • Pilc A.
        • Chaki S.
        • Nowak G.
        • Witkin J.M.
        Mood disorders: Regulation by metabotropic glutamate receptors.
        Biochem Pharmacol. 2008; 75: 997-1006
        • Lowery-Gionta E.G.
        • Crowley N.A.
        • Bukalo O.
        • Silverstein S.
        • Holmes A.
        • Kash T.L.
        Chronic stress dysregulates amygdalar output to the prefrontal cortex.
        Neuropharmacology. 2018; 139: 68-75
        • Zhang J.Y.
        • Liu T.H.
        • He Y.
        • Pan H.Q.
        • Zhang W.H.
        • Yin X.P.
        • et al.
        Chronic stress remodels synapses in an amygdala circuit-specific manner.
        Biol Psychiatry. 2019; 85: 189-201
        • DeLorenzo C.
        • Gallezot J.D.
        • Gardus J.
        • Yang J.
        • Planeta B.
        • Nabulsi N.
        • et al.
        In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [11C]ABP688 and [18F]FPEB.
        J Cereb Blood Flow Metab. 2017; 37: 2716-2727
        • Elmenhorst D.
        • Mertens K.
        • Kroll T.
        • Oskamp A.
        • Ermert J.
        • Elmenhorst E.M.
        • et al.
        Circadian variation of metabotropic glutamate receptor 5 availability in the rat brain.
        J Sleep Res. 2016; 25: 754-761
        • Cyranowski J.M.
        • Frank E.
        • Young E.
        • Shear M.K.
        Adolescent onset of the gender difference in lifetime rates of major depression: A theoretical model.
        Arch Gen Psychiatry. 2000; 57: 21-27
        • Albert P.R.
        Why is depression more prevalent in women?.
        J Psychiatry Neurosci. 2015; 40: 219-221

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      • Metabotropic Glutamate Receptor 5: A Potential Molecular Switch and Beyond
        Biological PsychiatryVol. 92Issue 2
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          Depression is one of the most common mental illnesses, and it poses a serious threat to human health and well-being. Conventional antidepressants have substantial variations in clinical treatment efficacy, and despite the U.S. Food and Drug Administration’s approval of esketamine for treatment-resistant depression, further fast-acting and effective therapies are urgently needed. Recent clinical and experimental studies have linked dysregulation of the glutamatergic system to depression. Glutamate neurotransmission is mediated by ionotropic and metabotropic glutamate receptors, and ionotropic AMPA and NMDA receptors have received extensive attention.
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