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Dysfunction of Glutamatergic Synaptic Transmission in Depression: Focus on AMPA Receptor Trafficking

  • Jin-Gang He
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Hai-Yun Zhou
    Affiliations
    Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
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  • Fang Wang
    Correspondence
    Fang Wang, M.D., Ph.D.
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Jian-Guo Chen
    Correspondence
    Address correspondence to Jian-Guo Chen, M.D., Ph.D.
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Open AccessPublished:March 08, 2022DOI:https://doi.org/10.1016/j.bpsgos.2022.02.007

      Abstract

      Pharmacological and anatomical evidence suggests that abnormal glutamatergic neurotransmission may be associated with the pathophysiology of depression. Compounds that act as NMDA receptor antagonists may be a potential treatment for depression, notably the rapid-acting agent ketamine. The rapid-acting and sustained antidepressant effects of ketamine rely on the activation of AMPA receptors (AMPARs). As the key elements of fast excitatory neurotransmission in the brain, AMPARs are crucially involved in synaptic plasticity and memory. Recent efforts have been directed toward investigating the bidirectional dysregulation of AMPAR-mediated synaptic transmission in depression. Here, we summarize the published evidence relevant to the dysfunction of AMPAR in stress conditions and review the recent progress toward the understanding of the involvement of AMPAR trafficking in the pathophysiology of depression, focusing on the roles of AMPAR auxiliary subunits, key AMPAR-interacting proteins, and posttranslational regulation of AMPARs. We also discuss new prospects for the development of improved therapeutics for depression.

      Keywords

      Major depressive disorder (MDD) is a severe psychiatric disorder affecting approximately 5% of the world population and contributing significantly to global economic and health burdens (
      • Malhi G.S.
      • Mann J.J.
      Depression.
      ,
      • König H.
      • König H.H.
      • Konnopka A.
      The excess costs of depression: A systematic review and meta-analysis.
      ). Clinical antidepressants, including selective serotonin reuptake inhibitors (SSRIs), are widely used for the treatment of depression. However, there is a significant time lag of several weeks before the benefit for patients with MDD, and approximately one third of patients do not experience therapeutic benefits following treatment with SSRIs (
      • Mrazek D.A.
      • Hornberger J.C.
      • Altar C.A.
      • Degtiar I.
      A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996–2013.
      ). Therefore, the development of robust and rapid-acting antidepressants is urgent to improve symptoms and suicidal ideation in patients with MDD.
      Glutamate is the major mediator of excitatory synaptic transmission in the mammalian brain. Glutamate released by the presynaptic terminal binds to and activates specialized ionotropic and metabotropic receptors in the postsynaptic membrane, producing wide-ranging effects on neuronal excitability. The role of the glutamatergic system in the pathophysiology and treatment of depression has been investigated (
      • Murrough J.W.
      • Abdallah C.G.
      • Mathew S.J.
      Targeting glutamate signalling in depression: Progress and prospects.
      ). The antidepressant effects of ketamine have attracted increasing attention owing to their rapid-acting and long-lasting effects. Although ketamine acts as an NMDA receptor (NMDAR) antagonist, its antidepressant effects may be independent of NMDAR inhibition and rely on the activation of AMPA receptors (AMPARs) (
      • Zanos P.
      • Moaddel R.
      • Morris P.J.
      • Georgiou P.
      • Fischell J.
      • Elmer G.I.
      • et al.
      NMDAR inhibition-independent antidepressant actions of ketamine metabolites.
      ,
      • Shinohara R.
      • Aghajanian G.K.
      • Abdallah C.G.
      Neurobiology of the rapid-acting antidepressant effects of ketamine: Impact and opportunities.
      ).
      AMPARs are composed of glutamate receptor subunits (GluA1–GluA4) that form tetramers (mainly GluA1/GluA2 and GluA2/GluA3 heteromers) to participate in excitatory neurotransmission and activity-dependent synaptic plasticity and synaptogenesis (
      • Wu Q.L.
      • Gao Y.
      • Li J.T.
      • Ma W.Y.
      • Chen N.H.
      The role of AMPARs composition and trafficking in synaptic plasticity and diseases [published online ahead of print Aug 26].
      ). In contrast to NMDARs, AMPARs are highly mobile, and their synaptic abundance is tightly regulated, such as trafficking to/from the synapse, mobility along the plasma membrane, and synaptic stabilization. The components of AMPAR subunits are developmentally regulated and region specific (
      • Schwenk J.
      • Baehrens D.
      • Haupt A.
      • Bildl W.
      • Boudkkazi S.
      • Roeper J.
      • et al.
      Regional diversity and developmental dynamics of the AMPA-receptor proteome in the mammalian brain.
      ). Chronic stress breaks the homeostasis of AMPAR trafficking via numerous protein molecules and signaling pathways, such as AMPAR auxiliary subunits, key AMPAR-interacting proteins, and posttranslational regulation of AMPARs. Chronic physical and psychological stress is a major risk factor for psychiatric disorders such as depression (
      • Hammen C.
      Stress and depression.
      ). Prolonged stress impairs neuronal structure and function and leads to psychiatric disorders. Several animal models of chronic stress have been established to explore the potential mechanism of depression, such as chronic social defeat stress (CSDS), chronic restraint stress (CRS), and chronic unpredictable stress (CUS) (
      • Gururajan A.
      • Reif A.
      • Cryan J.F.
      • Slattery D.A.
      The future of rodent models in depression research.
      ).
      This review presents an integrative overview of the current literature surrounding the disturbance of surface stability of AMPARs under stress conditions. It delineates the functional implications of this process in depression by focusing on the mechanisms of AMPAR trafficking in the pathophysiology, which will be helpful for identifying potential drug targets for the therapeutics of MDD.

      AMPAR-Mediated Synaptic Transmission in Depression

      Stress-induced alterations in AMPAR-mediated synaptic transmission result from changes in expression or subunit composition of AMPARs. However, opposite findings often appear in the literature (
      • Thompson S.M.
      • Kallarackal A.J.
      • Kvarta M.D.
      • Van Dyke A.M.
      • LeGates T.A.
      • Cai X.
      An excitatory synapse hypothesis of depression.
      ), which may be due to the considerable heterogeneity among brain regions and the variability of stress. We summarize functional changes in AMPARs in brain regions that are closely related to MDD based on preclinical and clinical studies (Table 1).
      Table 1Summary of AMPAR Expression in Preclinical Models of Depression and Patients With Depression
      AMPA ReceptorBrain RegionExpressionStress or SampleReferences
      Preclinical Studies
      GluANAcCSDS, FSS(
      • Pignatelli M.
      • Tejeda H.A.
      • Barker D.J.
      • Bontempi L.
      • Wu J.
      • Lopez A.
      • et al.
      Cooperative synaptic and intrinsic plasticity in a disynaptic limbic circuit drive stress-induced anhedonia and passive coping in mice.
      ,
      • Kim H.D.
      • Wei J.
      • Call T.
      • Quintus N.T.
      • Summers A.J.
      • Carotenuto S.
      • et al.
      Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens.
      ,
      • 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.
      )
      NAcCUS(
      • LeGates T.A.
      • Kvarta M.D.
      • Tooley J.R.
      • Francis T.C.
      • Lobo M.K.
      • Creed M.C.
      • Thompson S.M.
      Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses.
      )
      PFCCRS, CSDS(
      • Zhang R.X.
      • Han Y.
      • Chen C.
      • Xu L.Z.
      • Li J.L.
      • Chen N.
      • et al.
      EphB2 in the medial prefrontal cortex regulates vulnerability to stress.
      ,
      • Deng Z.F.
      • Zheng H.L.
      • Chen J.G.
      • Luo Y.
      • Xu J.F.
      • Zhao G.
      • et al.
      miR-214-3p targets β-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice.
      ,
      • Seo J.S.
      • Wei J.
      • Qin L.
      • Kim Y.
      • Yan Z.
      • Greengard P.
      Cellular and molecular basis for stress-induced depression.
      )
      GluA1PFCCRS, FST(
      • Sutton L.P.
      • Orlandi C.
      • Song C.
      • Oh W.C.
      • Muntean B.S.
      • Xie K.
      • et al.
      Orphan receptor GPR158 controls stress-induced depression.
      ,
      • 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.
      ,
      • Yuen E.Y.
      • Wei J.
      • Liu W.
      • Zhong P.
      • Li X.
      • Yan Z.
      Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex.
      )
      HippocampusLPS, CUS, CSDS(
      • Li M.X.
      • Zheng H.L.
      • Luo Y.
      • He J.G.
      • Wang W.
      • Han J.
      • et al.
      Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs.
      ,
      • 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.
      ,
      • Kallarackal A.J.
      • Kvarta M.D.
      • Cammarata E.
      • Jaberi L.
      • Cai X.
      • Bailey A.M.
      • Thompson S.M.
      Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses.
      ,
      • Sakai Y.
      • Li H.
      • Inaba H.
      • Funayama Y.
      • Ishimori E.
      • Kawatake-Kuno A.
      • et al.
      Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway.
      ,
      • Francija E.
      • Petrovic Z.
      • Brkic Z.
      • Mitic M.
      • Radulovic J.
      • Adzic M.
      Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression.
      ,
      • Duric V.
      • Banasr M.
      • Stockmeier C.A.
      • Simen A.A.
      • Newton S.S.
      • Overholser J.C.
      • et al.
      Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.
      )
      PFC, HippocampusCMS(
      • Toth E.
      • Gersner R.
      • Wilf-Yarkoni A.
      • Raizel H.
      • Dar D.E.
      • Richter-Levin G.
      • et al.
      Age-dependent effects of chronic stress on brain plasticity and depressive behavior.
      )
      NAcCSDS(
      • Vialou V.
      • Robison A.J.
      • Laplant Q.C.
      • Covington 3rd, H.E.
      • Dietz D.M.
      • Ohnishi Y.N.
      • et al.
      DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses.
      )
      AmygdalaCUS(
      • Chandran A.
      • Iyo A.H.
      • Jernigan C.S.
      • Legutko B.
      • Austin M.C.
      • Karolewicz B.
      Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress.
      )
      BLACSDS, FSS, CRS(
      • Yi E.S.
      • Oh S.
      • Lee J.K.
      • Leem Y.H.
      Chronic stress-induced dendritic reorganization and abundance of synaptosomal PKA-dependent CP-AMPA receptor in the basolateral amygdala in a mouse model of depression.
      ,
      • Zhou H.Y.
      • He J.G.
      • Hu Z.L.
      • Xue S.G.
      • Xu J.F.
      • Cui Q.Q.
      • et al.
      A-kinase anchoring Protein 150 and protein kinase A complex in the basolateral amygdala contributes to depressive-like behaviors induced by chronic restraint stress.
      ,
      • Kuniishi H.
      • Yamada D.
      • Wada K.
      • Yamada M.
      • Sekiguchi M.
      Stress induces insertion of calcium-permeable AMPA receptors in the OFC-BLA synapse and modulates emotional behaviours in mice.
      )
      GluA2PFCCRS, CUS(
      • Yuen E.Y.
      • Wei J.
      • Liu W.
      • Zhong P.
      • Li X.
      • Yan Z.
      Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex.
      ,
      • Wei J.
      • Cheng J.
      • Waddell N.J.
      • Wang Z.J.
      • Pang X.
      • Cao Q.
      • et al.
      DNA methyltransferase 3A is involved in the sustained effects of chronic stress on synaptic functions and behaviors.
      )
      HippocampusCSDS(
      • Li M.X.
      • Zheng H.L.
      • Luo Y.
      • He J.G.
      • Wang W.
      • Han J.
      • et al.
      Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs.
      ,
      • Umschweif G.
      • Medrihan L.
      • Guillén-Samander A.
      • Wang W.
      • Sagi Y.
      • Greengard P.
      Identification of Neurensin-2 as a novel modulator of emotional behavior.
      )
      HippocampusCRS(
      • McWhirt J.
      • Sathyanesan M.
      • Sampath D.
      • Newton S.S.
      Effects of restraint stress on the regulation of hippocampal glutamate receptor and inflammation genes in female C57BL/6 and BALB/c mice.
      )
      NAcCRS, CSDS(
      • Vialou V.
      • Robison A.J.
      • Laplant Q.C.
      • Covington 3rd, H.E.
      • Dietz D.M.
      • Ohnishi Y.N.
      • et al.
      DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses.
      ,
      • Lim B.K.
      • Huang K.W.
      • Grueter B.A.
      • Rothwell P.E.
      • Malenka R.C.
      Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens.
      )
      Patients With Depression
      GluAACCMDD(
      • Gibbons A.S.
      • Brooks L.
      • Scarr E.
      • Dean B.
      AMPA receptor expression is increased post-mortem samples of the anterior cingulate from subjects with major depressive disorder.
      )
      GluA1/3HippocampusMDD(
      • Duric V.
      • Banasr M.
      • Stockmeier C.A.
      • Simen A.A.
      • Newton S.S.
      • Overholser J.C.
      • et al.
      Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.
      )
      GluA1DLPFCMDD(
      • O’Connor J.A.
      • Hemby S.E.
      Elevated GRIA1 mRNA expression in layer II/III and V pyramidal cells of the DLPFC in schizophrenia.
      )
      GluA2NAcMDD(
      • Vialou V.
      • Robison A.J.
      • Laplant Q.C.
      • Covington 3rd, H.E.
      • Dietz D.M.
      • Ohnishi Y.N.
      • et al.
      DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses.
      )
      ACC, anterior cingulate cortex; AMPAR, AMPA receptor; BLA, basolateral amygdala; CMS, chronic mild stress; CRS, chronic restraint stress; CSDS, chronic social defeat stress; CUS, chronic unpredictable stress; DLPFC, dorsolateral prefrontal cortex; FSS, footshock stress; FST, forced swim test; LPS, lipopolysaccharide; MDD, major depressive disorder; NAc, nucleus accumbens; PFC, prefrontal cortex.

      Prefrontal Cortex

      The prefrontal cortex (PFC) is an important brain subregion in which the controllability of a stressor or the pleasantness of a stimulus can influence mood and reward (
      • Thompson S.M.
      • Kallarackal A.J.
      • Kvarta M.D.
      • Van Dyke A.M.
      • LeGates T.A.
      • Cai X.
      An excitatory synapse hypothesis of depression.
      ). Chronic stress induces the loss of dendritic spines in the PFC and a decrease in AMPAR expression, leading to the attenuation of AMPAR-mediated synaptic transmission (
      • Zhang R.X.
      • Han Y.
      • Chen C.
      • Xu L.Z.
      • Li J.L.
      • Chen N.
      • et al.
      EphB2 in the medial prefrontal cortex regulates vulnerability to stress.
      ,
      • Sutton L.P.
      • Orlandi C.
      • Song C.
      • Oh W.C.
      • Muntean B.S.
      • Xie K.
      • et al.
      Orphan receptor GPR158 controls stress-induced depression.
      ,
      • Deng Z.F.
      • Zheng H.L.
      • Chen J.G.
      • Luo Y.
      • Xu J.F.
      • Zhao G.
      • et al.
      miR-214-3p targets β-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice.
      ). Sutton et al. (
      • Sutton L.P.
      • Orlandi C.
      • Song C.
      • Oh W.C.
      • Muntean B.S.
      • Xie K.
      • et al.
      Orphan receptor GPR158 controls stress-induced depression.
      ) found that CUS increased the expression of orphan receptor GPR158 via a glucocorticoid-dependent manner. GPR158-induced activation of cAMP-dependent protein kinase A (PKA) may be responsible for the decreased phosphorylation of GluA1 and AMPAR-mediated synaptic transmission (
      • Sutton L.P.
      • Orlandi C.
      • Song C.
      • Oh W.C.
      • Muntean B.S.
      • Xie K.
      • et al.
      Orphan receptor GPR158 controls stress-induced depression.
      ). In the CSDS model, reduction of the ephrin B2 receptor and activation of the miR-214-β-catenin signaling pathway in the mPFC induce a decrease in AMPAR and spine remodeling (
      • Zhang R.X.
      • Han Y.
      • Chen C.
      • Xu L.Z.
      • Li J.L.
      • Chen N.
      • et al.
      EphB2 in the medial prefrontal cortex regulates vulnerability to stress.
      ,
      • Deng Z.F.
      • Zheng H.L.
      • Chen J.G.
      • Luo Y.
      • Xu J.F.
      • Zhao G.
      • et al.
      miR-214-3p targets β-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice.
      ). A potential involvement of the mTOR (mechanistic target of rapamycin) signaling pathway in depression has been suggested by postmortem studies, which report a significant reduction in mTOR and S6K protein levels in the PFC of subjects with MDD (
      • Jernigan C.S.
      • Goswami D.B.
      • Austin M.C.
      • Iyo A.H.
      • Chandran A.
      • Stockmeier C.A.
      • Karolewicz B.
      The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder.
      ). In the chronic behavioral despair mouse model of depression, the decreased Homer1a-mGluR5 signaling downregulates AMPAR function via damping GluA1 protein translation and trafficking (
      • 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.
      ). More detailed studies have found that selective loss of p11 in the dopamine D2 receptor–expressing glutamatergic neurons in the prelimbic cortex induces the attenuation of AMPAR-mediated synaptic transmission in the CRS model, which can be restored by antidepressants, such as fluoxetine or imipramine (
      • Seo J.S.
      • Wei J.
      • Qin L.
      • Kim Y.
      • Yan Z.
      • Greengard P.
      Cellular and molecular basis for stress-induced depression.
      ). The biochemical changes in AMPAR expression under stress conditions are varied among different reports. Some studies observed a decrease in both GluA1 and GluA2 expression (
      • Zhang R.X.
      • Han Y.
      • Chen C.
      • Xu L.Z.
      • Li J.L.
      • Chen N.
      • et al.
      EphB2 in the medial prefrontal cortex regulates vulnerability to stress.
      ,
      • Yuen E.Y.
      • Wei J.
      • Liu W.
      • Zhong P.
      • Li X.
      • Yan Z.
      Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex.
      ,
      • Wei J.
      • Xiong Z.
      • Lee J.B.
      • Cheng J.
      • Duffney L.J.
      • Matas E.
      • Yan Z.
      Histone modification of Nedd4 ubiquitin ligase controls the loss of AMPA receptors and cognitive impairment induced by repeated stress.
      ). However, other studies observed a specific decrease in GluA1 or GluA2 (
      • Sutton L.P.
      • Orlandi C.
      • Song C.
      • Oh W.C.
      • Muntean B.S.
      • Xie K.
      • et al.
      Orphan receptor GPR158 controls stress-induced depression.
      ,
      • 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.
      ,
      • Wei J.
      • Cheng J.
      • Waddell N.J.
      • Wang Z.J.
      • Pang X.
      • Cao Q.
      • et al.
      DNA methyltransferase 3A is involved in the sustained effects of chronic stress on synaptic functions and behaviors.
      ). In addition, chronic stress also weakens the miniature excitatory postsynaptic current, which is a critical indicator of AMPAR function. In these studies, GluA1- or GluA2-containing receptor–mediated currents cannot be distinguished due to the absence of specific AMPAR blockers (
      • Deng Z.F.
      • Zheng H.L.
      • Chen J.G.
      • Luo Y.
      • Xu J.F.
      • Zhao G.
      • et al.
      miR-214-3p targets β-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice.
      ,
      • Seo J.S.
      • Wei J.
      • Qin L.
      • Kim Y.
      • Yan Z.
      • Greengard P.
      Cellular and molecular basis for stress-induced depression.
      ). Seo et al. (
      • Seo J.S.
      • Wei J.
      • Qin L.
      • Kim Y.
      • Yan Z.
      • Greengard P.
      Cellular and molecular basis for stress-induced depression.
      ) showed that AMPAR-mediated glutamatergic transmission was depressed only in D2 receptor–expressing glutamatergic neurons in the PFC. Wei et al. (
      • Wei J.
      • Zhong P.
      • Qin L.
      • Tan T.
      • Yan Z.
      Chemicogenetic restoration of the prefrontal cortex to amygdala pathway ameliorates stress-induced deficits.
      ) observed diminished glutamatergic transmission in pyramidal neurons projecting to the basolateral amygdala (BLA) in animals exposed to prolonged severe stress, which can be restored by chemogenetic activation of pyramidal neurons in the PFC. Collectively, these results reveal impaired AMPAR-mediated synaptic transmission in the PFC under chronic stress conditions, which is closely related to depressive-like behaviors in rodents.

      Nucleus Accumbens

      More than 95% of neurons in the nucleus accumbens (NAc) are primarily composed of two types of medium spiny neurons (MSNs) enriched with D1 or D2 receptors (D1-MSNs and D2-MSNs, respectively). CSDS induces decreased binding of ΔFOSB to the GluA2 promoter and the subsequent higher proportion of GluA2-lacking AMPARs in susceptible mice followed by CSDS (
      • Vialou V.
      • Robison A.J.
      • Laplant Q.C.
      • Covington 3rd, H.E.
      • Dietz D.M.
      • Ohnishi Y.N.
      • et al.
      DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses.
      ). Lim et al. (
      • Lim B.K.
      • Huang K.W.
      • Grueter B.A.
      • Rothwell P.E.
      • Malenka R.C.
      Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens.
      ) showed that endocytosis of GluA2 and insertion of GluA2-lacking AMPARs were specifically restricted to D1-MSNs but not D2-MSNs after CRS owing to the activation of melanocortin 4 receptor and the downstream exchange proteins activated by cyclic AMP. The NAc is critical to integrating input from the hippocampus and ventral tegmental area (
      • Smith K.S.
      • Berridge K.C.
      • Aldridge J.W.
      Disentangling pleasure from incentive salience and learning signals in brain reward circuitry.
      ). Chronic stress also decreases the AMPAR/NMDAR ratio, an index of change in postsynaptic function, on D1-MSNs receiving projections from the hippocampus, which can be rescued by fluoxetine treatment (
      • Lim B.K.
      • Huang K.W.
      • Grueter B.A.
      • Rothwell P.E.
      • Malenka R.C.
      Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens.
      ,
      • LeGates T.A.
      • Kvarta M.D.
      • Tooley J.R.
      • Francis T.C.
      • Lobo M.K.
      • Creed M.C.
      • Thompson S.M.
      Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses.
      ).
      It is worth noting that some conflicting results exist on the excitatory synaptic transmission on D1-MSNs in the NAc under chronic stress. Ventral hippocampal synapses onto D1-MSNs are potentiated by footshock stress, and the elevated AMPAR/NMDAR ratio is due to increased AMPAR-mediated synaptic currents (
      • Pignatelli M.
      • Tejeda H.A.
      • Barker D.J.
      • Bontempi L.
      • Wu J.
      • Lopez A.
      • et al.
      Cooperative synaptic and intrinsic plasticity in a disynaptic limbic circuit drive stress-induced anhedonia and passive coping in mice.
      ). Kim et al. (
      • Kim H.D.
      • Wei J.
      • Call T.
      • Quintus N.T.
      • Summers A.J.
      • Carotenuto S.
      • et al.
      Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens.
      ) also found that CSDS increased AMPAR-mediated neurotransmission on D1-MSNs, which received projections from the ventral tegmental area. The potent AMPAR function is due to the cell-specific upregulation of Shisa6, a transmembrane adapter protein of AMPARs (
      • Kim H.D.
      • Wei J.
      • Call T.
      • Quintus N.T.
      • Summers A.J.
      • Carotenuto S.
      • et al.
      Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens.
      ). However, Francis et al. (
      • 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.
      ,
      • 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.
      ) found no significant changes in the amplitude of AMPAR-mediated synaptic currents on D1-MSNs in susceptible mice, but the frequency was decreased. They showed that an early growth response family member, EGR3, mediated the susceptibility of mice to stress by controlling stress-driven dendritic morphological adaptations in D1-MSNs. EGR3-mediated dendritic changes lead to functional alterations in excitatory synaptic transmission (
      • 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.
      ). These conflicting results highlight the complex nature of the NAc circuit in depression. The impact of stress on MSNs in the NAc varies with cell specificity.

      Hippocampus

      The hippocampus is a key brain region in the neuronal circuit that regulates cognitive and emotional behaviors. Chronic stress (CSDS or CRS) decreases AMPAR expression and miniature excitatory postsynaptic current amplitude in the hippocampus (
      • Li M.X.
      • Zheng H.L.
      • Luo Y.
      • He J.G.
      • Wang W.
      • Han J.
      • et al.
      Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs.
      ,
      • 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.
      ,
      • Umschweif G.
      • Medrihan L.
      • Guillén-Samander A.
      • Wang W.
      • Sagi Y.
      • Greengard P.
      Identification of Neurensin-2 as a novel modulator of emotional behavior.
      ). Ma et al. (
      • 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.
      ) showed that CUS induced reduction in spine density, dendritic complexity, and synaptosomal AMPARs in the ventral CA1. This pathological changes were reversed by stimulation of posterior BLA–ventral CA1 innervation via chemogenetics or administration of cannabidiol, indicating the dependence of neuronal activity and circuit-specific regulation (
      • 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.
      ). In CSDS or CUS models, the phosphorylation of AMPAR subunit GluA1 is also reduced, leading to a decrease in synaptosomal AMPAR level (
      • 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.
      ,
      • Kallarackal A.J.
      • Kvarta M.D.
      • Cammarata E.
      • Jaberi L.
      • Cai X.
      • Bailey A.M.
      • Thompson S.M.
      Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses.
      ,
      • Sakai Y.
      • Li H.
      • Inaba H.
      • Funayama Y.
      • Ishimori E.
      • Kawatake-Kuno A.
      • et al.
      Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway.
      ). The decrease in GluA1 expression relies on the CaMKIIβ-mediated phosphorylation of GluA1 or the AMPAR auxiliary subunit TARP-γ8 (
      • Sakai Y.
      • Li H.
      • Inaba H.
      • Funayama Y.
      • Ishimori E.
      • Kawatake-Kuno A.
      • et al.
      Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway.
      ). The neurogenesis hypothesis of depression suggests that chronic antidepressant treatment, such as by using SSRIs, alleviates depressive-like behaviors through increasing neurogenesis in the hippocampus. However, more current literature has disputed those findings and concludes that neurogenesis can be affected by stress and antidepressants under certain conditions (
      • Samuels B.A.
      • Hen R.
      Neurogenesis and affective disorders.
      ,
      • Hanson N.D.
      • Owens M.J.
      • Nemeroff C.B.
      Depression, antidepressants, and neurogenesis: A critical reappraisal.
      ). Neuropeptides and anti-inflammatory action may be relevant to the mechanism of action of SSRIs (
      • Gołyszny M.
      • Obuchowicz E.
      Are neuropeptides relevant for the mechanism of action of SSRIs?.
      ,
      • Gałecki P.
      • Mossakowska-Wójcik J.
      • Talarowska M.
      The anti-inflammatory mechanism of antidepressants—SSRIs, SNRIs.
      ). In addition, enhanced AMPAR-mediated synaptic transmission in the hippocampus also responds to chronic antidepressant treatment, underlying the mechanism for ameliorating depressive-like behaviors in mice (
      • Umschweif G.
      • Medrihan L.
      • Guillén-Samander A.
      • Wang W.
      • Sagi Y.
      • Greengard P.
      Identification of Neurensin-2 as a novel modulator of emotional behavior.
      ,
      • Kallarackal A.J.
      • Kvarta M.D.
      • Cammarata E.
      • Jaberi L.
      • Cai X.
      • Bailey A.M.
      • Thompson S.M.
      Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses.
      ,
      • Cai X.
      • Kallarackal A.J.
      • Kvarta M.D.
      • Goluskin S.
      • Gaylor K.
      • Bailey A.M.
      • et al.
      Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression.
      ). Recent studies also show that the dynamic expression of AMPARs in specific interneurons in the dentate gyrus responds to stress-induced depressive-like behaviors (
      • Umschweif G.
      • Medrihan L.
      • Guillén-Samander A.
      • Wang W.
      • Sagi Y.
      • Greengard P.
      Identification of Neurensin-2 as a novel modulator of emotional behavior.
      ,
      • Umschweif G.
      • Medrihan L.
      • McCabe K.A.
      • Sagi Y.
      • Greengard P.
      Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants.
      ). CSDS represses the SMARCA3/Neurensin-2 pathway in cholecystokinin- or parvalbumin-expressing interneurons to induce endocytosis of AMPARs (
      • Umschweif G.
      • Medrihan L.
      • Guillén-Samander A.
      • Wang W.
      • Sagi Y.
      • Greengard P.
      Identification of Neurensin-2 as a novel modulator of emotional behavior.
      ,
      • Umschweif G.
      • Medrihan L.
      • McCabe K.A.
      • Sagi Y.
      • Greengard P.
      Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants.
      ). In addition, activation of the SMARCA3/Neurensin-2 pathway and subsequent AMPAR localization to synapses in parvalbumin-expressing interneurons mediates the response to chronic antidepressant treatment (
      • Umschweif G.
      • Medrihan L.
      • McCabe K.A.
      • Sagi Y.
      • Greengard P.
      Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants.
      ). Regular exercise-induced neurophysiological adaptation is beneficial to multiple brain functions such as cognition and mood (
      • Fernandes J.
      • Arida R.M.
      • Gomez-Pinilla F.
      Physical exercise as an epigenetic modulator of brain plasticity and cognition.
      ). Leem et al. (
      • Leem Y.H.
      • Park J.S.
      • Chang H.
      • Park J.
      • Kim H.S.
      Exercise prevents memory consolidation defects via enhancing prolactin responsiveness of CA1 neurons in mice under chronic stress.
      ) found that regular exercise improved prolactin responsiveness in the hippocampal CA1 region, which led to prolactin-dependent enhancement in phosphorylated signal transducer and restored decreased GluA1 expression. These lines of evidence suggest that chronic stress weakens AMPAR-mediated synaptic transmission in diverse cell types in the hippocampus. Recovery of the deficit in synaptic transmission may be the key target of antidepressants.

      Amygdala

      The amygdala is a series of nuclei complexes and usually is divided into the BLA, the medial amygdala, and the central amygdala. Hyperactivity of the amygdala contributes to stress-induced neuropsychiatric disorders, such as anxiety and depression (
      • Rosenkranz J.A.
      • Venheim E.R.
      • Padival M.
      Chronic stress causes amygdala hyperexcitability in rodents.
      ). It is shown that GluA1 phosphorylation in the BLA synaptosome is increased in a PKA-dependent manner after exposure to chronic stress, leading to the insertion of GluA1 (
      • Yi E.S.
      • Oh S.
      • Lee J.K.
      • Leem Y.H.
      Chronic stress-induced dendritic reorganization and abundance of synaptosomal PKA-dependent CP-AMPA receptor in the basolateral amygdala in a mouse model of depression.
      ,
      • Zhou H.Y.
      • He J.G.
      • Hu Z.L.
      • Xue S.G.
      • Xu J.F.
      • Cui Q.Q.
      • et al.
      A-kinase anchoring Protein 150 and protein kinase A complex in the basolateral amygdala contributes to depressive-like behaviors induced by chronic restraint stress.
      ,
      • Kuniishi H.
      • Yamada D.
      • Wada K.
      • Yamada M.
      • Sekiguchi M.
      Stress induces insertion of calcium-permeable AMPA receptors in the OFC-BLA synapse and modulates emotional behaviours in mice.
      ). Endogenous cannabinoid signaling modulates glutamatergic neurotransmission in the BLA. Chronic stress and corticosterone treatment reduce cannabinoid receptor type 1–mediated attenuation of glutamatergic synaptic transmission in the BLA through presynaptic mechanisms (
      • Chandran A.
      • Iyo A.H.
      • Jernigan C.S.
      • Legutko B.
      • Austin M.C.
      • Karolewicz B.
      Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress.
      ,
      • Shen C.J.
      • Zheng D.
      • Li K.X.
      • Yang J.M.
      • Pan H.Q.
      • Yu X.D.
      • et al.
      Cannabinoid CB 1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior.
      ). Another study has found that CUS exposure decreases the phosphorylation of mTOR and its downstream signaling components extracellular signal–regulated kinases 1/2 and GluA1 (
      • Chandran A.
      • Iyo A.H.
      • Jernigan C.S.
      • Legutko B.
      • Austin M.C.
      • Karolewicz B.
      Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress.
      ). In this study, the whole amygdala was not subdivided into the BLA subregion, which may explain the discrepancy.
      Taken together, the preclinical available data suggest that region- and subunit-specific changes in AMPAR-mediated synaptic transmission are closely related to depressive-like behaviors. Chronic stress induces AMPAR-mediated transmission in the PFC and hippocampus but potentiates AMPAR-mediated transmission in the amygdala.

      Clinical Study

      There is relatively less AMPAR-related research in postmortem studies in MDD compared with the abundant results in animal models. These clinical and preclinical results are not always consistent. For example, different from the reduction in preclinical animal models, AMPAR expression is increased in the PFC in depression and postmortem studies (
      • O’Connor J.A.
      • Hemby S.E.
      Elevated GRIA1 mRNA expression in layer II/III and V pyramidal cells of the DLPFC in schizophrenia.
      ,
      • Gibbons A.S.
      • Brooks L.
      • Scarr E.
      • Dean B.
      AMPA receptor expression is increased post-mortem samples of the anterior cingulate from subjects with major depressive disorder.
      ,
      • Gray A.L.
      • Hyde T.M.
      • Deep-Soboslay A.
      • Kleinman J.E.
      • Sodhi M.S.
      Sex differences in glutamate receptor gene expression in major depression and suicide.
      ). The paradoxical results between preclinical and clinical studies may be due to the heterogeneity of samples. The preclinical studies mostly analyze the mPFC sample, while the clinical data mainly come from the dorsolateral PFC and anterior cingulate cortex. Furthermore, the subjects were not drug naïve, and antidepressant treatment may have an impact on the results. Moreover, there may be physiological changes in the postmortem studies. Therefore, detecting changes in AMPARs in living human brains would confirm the postmortem studies. Recently, Miyazaki et al. (
      • Miyazaki T.
      • Nakajima W.
      • Hatano M.
      • Shibata Y.
      • Kuroki Y.
      • Arisawa T.
      • et al.
      Visualization of AMPA receptors in living human brain with positron emission tomography.
      ) developed a positron emission tomography tracer, [11C]K-2, for AMPARs in living human brain. The increased tracer uptake can be detected in the epileptogenic focus of patients with epilepsy, which was correlated with the density of AMPAR protein examined by biochemical study after surgery. With this tracer, we will explore the number and function of AMPARs in the living human brains of patients with MDD.

      AMPAR Trafficking–Related Protein in Depression

      Functional AMPARs are assembled from four core subunits (GluA1–GluA4) with different combinations and additional proteins, such as AMPAR auxiliary subunits and AMPAR trafficking–related protein. AMPAR-interacting proteins exhibit different roles in regulating AMPAR trafficking and function, attracting more and more attention over the past few years. Their temporally and spatially regulated expression leads to different combinations according to brain region and neuronal type and also provides a molecular framework underlying the spatiotemporal-specific features of AMPAR trafficking (
      • Schwenk J.
      • Baehrens D.
      • Haupt A.
      • Bildl W.
      • Boudkkazi S.
      • Roeper J.
      • et al.
      Regional diversity and developmental dynamics of the AMPA-receptor proteome in the mammalian brain.
      ,
      • Maher M.P.
      • Matta J.A.
      • Gu S.
      • Seierstad M.
      • Bredt D.S.
      Getting a handle on neuropharmacology by targeting receptor-associated proteins.
      ).

      AMPAR Auxiliary Subunits

      The category of AMPAR auxiliary subunits comprises the family of TARPs, Shisas, cornichon homolog proteins, synapse differentiation-induced gene 1/4, and germ cell-specific gene 1 like protein (
      • Kamalova A.
      • Nakagawa T.
      AMPA receptor structure and auxiliary subunits.
      ). Auxiliary subunits interact directly with AMPARs and affect various functions, such as channel gating, conductance, subunit composition, and trafficking (
      • Jacobi E.
      • von Engelhardt J.
      Modulation of information processing by AMPA receptor auxiliary subunits.
      ).
      TARPs are the first identified auxiliary proteins for neuronal AMPARs (
      • Kato A.S.
      • Gill M.B.
      • Yu H.
      • Nisenbaum E.S.
      • Bredt D.S.
      TARPs differentially decorate AMPA receptors to specify neuropharmacology.
      ). TARPs are enriched in the postsynaptic density and are important for surface expression of AMPARs in the brain regions where they are expressed (
      • Tomita S.
      • Chen L.
      • Kawasaki Y.
      • Petralia R.S.
      • Wenthold R.J.
      • Nicoll R.A.
      • Bredt D.S.
      Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins.
      ,
      • Tomita S.
      • Fukata M.
      • Nicoll R.A.
      • Bredt D.S.
      Dynamic interaction of stargazin-like TARPs with cycling AMPA receptors at synapses.
      ). The deletion of TARP-γ2 leads to a total loss of surface AMPARs on cerebellar granule cells, and TARP-γ8 loss leads to about 85% reduction of AMPARs in the hippocampus (
      • Chen L.
      • Chetkovich D.M.
      • Petralia R.S.
      • Sweeney N.T.
      • Kawasaki Y.
      • Wenthold R.J.
      • et al.
      Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms.
      ,
      • Rouach N.
      • Byrd K.
      • Petralia R.S.
      • Elias G.M.
      • Adesnik H.
      • Tomita S.
      • et al.
      TARP gamma-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity.
      ). TARP-γ8 knockout mice also exhibit reduced marble-burying behaviors and immobility time, indicating its anxiolytic and antidepressant effects. Furthermore, the antidepressant-like effects of LY392098, an AMPAR potentiator, are abolished in TARP-γ8 knockout mice (
      • Gleason S.D.
      • Kato A.
      • Bui H.H.
      • Thompson L.K.
      • Valli S.N.
      • Stutz P.V.
      • et al.
      Inquiries into the Biological Significance of Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8 Through Investigations of TARP γ-8 Null mice.
      ). Recently, Sakai et al. (
      • Sakai Y.
      • Li H.
      • Inaba H.
      • Funayama Y.
      • Ishimori E.
      • Kawatake-Kuno A.
      • et al.
      Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway.
      ) demonstrated that CaMKIIβ-mediated TARP-γ8 phosphorylation enhanced the expression of GluA1 in hippocampal CA1 neurons to promote stress resilience. These studies indicate the role of the TARP-γ8–AMPAR complex in depression. In view of the predominant expression of TARP-γ8 in the hippocampus, compounds specific for AMPARs associated with TARPγ-8 are being developed, leading to the discovery of LY3130481 and JNJ55511118, the antagonists of TARPγ-8–containing AMPARs (
      • Kato A.S.
      • Burris K.D.
      • Gardinier K.M.
      • Gernert D.L.
      • Porter W.J.
      • Reel J.
      • et al.
      Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.
      ,
      • Dohrke J.N.
      • Watson J.F.
      • Birchall K.
      • Greger I.H.
      Characterizing the binding and function of TARP γ8-selective AMPA receptor modulators.
      ). JNJ55511118 treatment increased the susceptibility to stress (
      • Sakai Y.
      • Li H.
      • Inaba H.
      • Funayama Y.
      • Ishimori E.
      • Kawatake-Kuno A.
      • et al.
      Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway.
      ). More importantly, in contrast to perampanel, the blocker of AMPARs in all brain regions, LY3130481 significantly reduces the incidence of side effects such as dizziness (
      • Kato A.S.
      • Burris K.D.
      • Gardinier K.M.
      • Gernert D.L.
      • Porter W.J.
      • Reel J.
      • et al.
      Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.
      ). Considering a better understanding of the precise stoichiometry and architecture of the TARP-γ8–AMPAR complex through cryoelectron microscopy in recent years (
      • Herguedas B.
      • Watson J.F.
      • Ho H.
      • Cais O.
      • García-Nafría J.
      • Greger I.H.
      Architecture of the heteromeric GluA1/2 AMPA receptor in complex with the auxiliary subunit TARP γ8.
      ,
      • Yu J.
      • Rao P.
      • Clark S.
      • Mitra J.
      • Ha T.
      • Gouaux E.
      Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition.
      ), we look forward to more JNJ55511118-like drugs being developed.
      Shisas constitute a family of four proteins that influence the trafficking and subcellular localization of AMPARs (
      • von Engelhardt J.
      AMPA receptor auxiliary proteins of the CKAMP family.
      ). Shisa9 has been recently identified as a gene related to major depression by large-scale genome-wide association study (
      • Wray N.R.
      • Ripke S.
      • Mattheisen M.
      • Trzaskowski M.
      • Byrne E.M.
      • Abdellaoui A.
      • et al.
      Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
      ). Shisa6 is expressed in the principal cell layers of the hippocampus and in the Purkinje layer of the cerebellum (
      • Farrow P.
      • Khodosevich K.
      • Sapir Y.
      • Schulmann A.
      • Aslam M.
      • Stern-Bach Y.
      • et al.
      Auxiliary subunits of the CKAMP family differentially modulate AMPA receptor properties.
      ,
      • Klaassen R.V.
      • Stroeder J.
      • Coussen F.
      • Hafner A.S.
      • Petersen J.D.
      • Renancio C.
      • et al.
      Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity.
      ). A recent study has found that chronic stress increased Shisa6 expression in D1-MSNs in the NAc, contributing to the depressive-like phenotypes of susceptible mice (
      • Kim H.D.
      • Wei J.
      • Call T.
      • Quintus N.T.
      • Summers A.J.
      • Carotenuto S.
      • et al.
      Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens.
      ). Cell-type action of Shisa6, which directly modulates excitatory synaptic transmission that encodes aversive information, identifies the protein as a potential antidepressant target.

      AMPAR–Interacting Proteins

      The four AMPAR subunits (GluA1–GluA4) are embedded into a dynamic network of distinct sets of interacting proteins. Many of these proteins are known to modulate receptor gating, trafficking, and subcellular localization, including direct and indirect protein-protein interactions.
      AMPAR subunits GluA1 and GluA3 share a common sequence at the end of their C-terminus through which they can interact with PDZ domain–containing proteins (
      • Dong H.
      • O’Brien R.J.
      • Fung E.T.
      • Lanahan A.A.
      • Worley P.F.
      • Huganir R.L.
      GRIP: A synaptic PDZ domain-containing protein that interacts with AMPA receptors.
      ). Two groups have been identified so far: the glutamate receptor–interacting protein family of proteins and PICK1 (
      • Xia J.
      • Zhang X.
      • Staudinger J.
      • Huganir R.L.
      Clustering of AMPA receptors by the synaptic PDZ domain-containing protein PICK1.
      ). Grip1 knockout mice exhibit impaired hippocampal long-term potentiation, as well as deficits in learning and memory, which is associated with decreased phosphorylation of GluA2 (
      • Tan H.L.
      • Chiu S.L.
      • Zhu Q.
      • Huganir R.L.
      GRIP1 regulates synaptic plasticity and learning and memory.
      ). GRIP1/2 double knockout mice show anxiety behavior and increased sociability and preference for social novelty (
      • Mejias R.
      • Chiu S.L.
      • Han M.
      • Rose R.
      • Gil-Infante A.
      • Zhao Y.
      • et al.
      Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum.
      ). Moreover, CUS increases the expression of GRIP1 in the PFC (
      • Barko K.
      • Paden W.
      • Cahill K.M.
      • Seney M.L.
      • Logan R.W.
      Sex-specific effects of stress on mood-related gene expression.
      ). It is well established that PICK1-GluA2 interaction is required for both hippocampal and cerebellar long-term depression (
      • Volk L.
      • Kim C.H.
      • Takamiya K.
      • Yu Y.
      • Huganir R.L.
      Developmental regulation of protein interacting with C kinase 1 (PICK1) function in hippocampal synaptic plasticity and learning.
      ,
      • Anggono V.
      • Koç-Schmitz Y.
      • Widagdo J.
      • Kormann J.
      • Quan A.
      • Chen C.M.
      • et al.
      PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression.
      ). PICK1 polymorphisms may be associated with cognitive impairment in patients with schizophrenia (
      • Chen Y.T.
      • Lin C.H.
      • Huang C.H.
      • Liang W.M.
      • Lane H.Y.
      PICK1 genetic variation and cognitive function in patients with schizophrenia.
      ). In addition, PICK1 knockout mice show attenuated reward-related behaviors characterized by decreased behavioral sensitization to a single injection of cocaine and diminished cocaine intake in a self-administration paradigm (
      • Jensen K.L.
      • Sørensen G.
      • Dencker D.
      • Owens W.A.
      • Rahbek-Clemmensen T.
      • Brett Lever M.
      • et al.
      PICK1-deficient mice exhibit impaired response to cocaine and dysregulated dopamine homeostasis.
      ).
      N-ethylmaleimide sensitive factor (NSF) interacts with the C-terminus of GluA2. Blockade of GluA2-NSF interaction results in decreased AMPAR-mediated excitatory postsynaptic currents, supporting a role of NSF in the synaptic abundance of GluA2-containing AMPARs (
      • Nishimune A.
      • Isaac J.T.
      • Molnar E.
      • Noel J.
      • Nash S.R.
      • Tagaya M.
      • et al.
      NSF binding to GluR2 regulates synaptic transmission.
      ), as well as its rapid incorporation and stabilization at synapses (
      • Beretta F.
      • Sala C.
      • Saglietti L.
      • Hirling H.
      • Sheng M.
      • Passafaro M.
      NSF interaction is important for direct insertion of GluR2 at synaptic sites.
      ). Moreover, infusion of a specific peptide, TAT-pep-R845A, which disrupts GluA2-NSF interaction, inhibits the formation of fear memory in the lateral amygdala and increased the locomotor response of rats to cocaine in the NAc (
      • Joels G.
      • Lamprecht R.
      Interaction between N-ethylmaleimide-sensitive factor and GluR2 is essential for fear memory formation in lateral amygdala.
      ,
      • Lu H.F.
      • Wu P.F.
      • Yang Y.J.
      • Xiao W.
      • Fan J.
      • Liu J.
      • et al.
      Interactions between N-ethylmaleimide-sensitive factor and GluR2 in the nucleus accumbens contribute to the expression of locomotor sensitization to cocaine.
      ). Exposure to stressful events increases the synthesis and release of glucocorticoids. Xiong et al. (
      • Xiong H.
      • Cassé F.
      • Zhou M.
      • Xiong Z.Q.
      • Joels M.
      • Martin S.
      • Krugers H.J.
      Interactions between N-Ethylmaleimide-sensitive factor and GluA2 contribute to effects of glucocorticoid hormones on AMPA receptor function in the rodent hippocampus.
      ) found that corticosterone increases the synaptic transmission and surface expression of AMPARs in hippocampal neurons, which was also prevented by TAT-pep-R845A.
      Syndapin is an F-BAR and SH3 domain–containing protein that is capable of remodeling the plasma membrane and mediating protein-protein interactions. Syndapin-1 associates with AMPARs via an interaction with PICK1 and regulates the activity-dependent endocytosis of AMPARs (
      • Anggono V.
      • Koç-Schmitz Y.
      • Widagdo J.
      • Kormann J.
      • Quan A.
      • Chen C.M.
      • et al.
      PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression.
      ,
      • Widagdo J.
      • Fang H.
      • Jang S.E.
      • Anggono V.
      PACSIN1 regulates the dynamics of AMPA receptor trafficking.
      ). Patients with schizophrenia or bipolar disorder display reduced levels of syndapin-1 protein in the dorsolateral PFC (
      • Pennington K.
      • Beasley C.L.
      • Dicker P.
      • Fagan A.
      • English J.
      • Pariante C.M.
      • et al.
      Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder.
      ,
      • Koch N.
      • Koch D.
      • Krueger S.
      • Tröger J.
      • Sabanov V.
      • Ahmed T.
      • et al.
      Syndapin I loss-of-function in mice leads to schizophrenia-like symptoms.
      ). Targeted multiplexed proteomic research also found that acute ketamine treatment induced the expression of syndapin-1 in the hippocampus of rats (
      • Wesseling H.
      • Rahmoune H.
      • Tricklebank M.
      • Guest P.C.
      • Bahn S.
      A targeted multiplexed proteomic investigation identifies ketamine-induced changes in immune markers in rat serum and expression changes in protein kinases/phosphatases in rat brain.
      ).
      SAP97 protein belongs to AMPAR native macromolecular complexes (
      • Schwenk J.
      • Harmel N.
      • Brechet A.
      • Zolles G.
      • Berkefeld H.
      • Müller C.S.
      • et al.
      High-resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes.
      ). SAP97 specifically binds to GluA1 but not GluA2 through GluA4, which depends on a small sequence outside of PDZ-binding sequence (
      • Cai C.
      • Coleman S.K.
      • Niemi K.
      • Keinänen K.
      Selective binding of synapse-associated protein 97 to GluR-A alpha-amino-5-hydroxy-3-methyl-4-isoxazole propionate receptor subunit is determined by a novel sequence motif.
      ). SAP97 appears to be involved in the regulation of AMPAR trafficking between extrasynaptic and synaptic pools. Upregulation of SAP97 was negatively correlated with hippocampal long-term potentiation, contributing to the deficits of learning and memory (
      • Sim S.E.
      • Lim C.S.
      • Kim J.I.
      • Seo D.
      • Chun H.
      • Yu N.K.
      • et al.
      The brain-enriched microRNA miR-9-3p regulates synaptic plasticity and memory.
      ). Ketamine treatment reduces the expression of SAP97 in the medial PFC and hippocampus of rats (
      • Caffino L.
      • Piva A.
      • Giannotti G.
      • Di Chio M.
      • Mottarlini F.
      • Venniro M.
      • et al.
      Ketamine self-administration reduces the homeostasis of the glutamate synapse in the rat brain.
      ,
      • Piva A.
      • Caffino L.
      • Mottarlini F.
      • Pintori N.
      • Castillo Díaz F.
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      Metaplastic effects of ketamine and MK-801 on glutamate receptors expression in rat medial prefrontal cortex and hippocampus.
      ).

      Posttranslational Regulation of AMPAR Trafficking and Function

      Exocytosis, endocytosis, and channel gating of AMPARs are dynamically regulated by AMPAR-interacting proteins and various reversible posttranslational modifications that occur on the cytoplasmic domains of AMPAR subunits. The kinases and phosphorylation sites on AMPAR subunits and their roles in receptor trafficking and function have been intensively studied (
      • Lu W.
      • Roche K.W.
      Posttranslational regulation of AMPA receptor trafficking and function.
      ,
      • Wang J.Q.
      • Guo M.L.
      • Jin D.Z.
      • Xue B.
      • Fibuch E.E.
      • Mao L.M.
      Roles of subunit phosphorylation in regulating glutamate receptor function.
      ). Several protein kinases, including CaMKII, PKA, and protein kinase C, are critical modulators of biophysical properties and activity-dependent AMPAR trafficking (
      • Wang J.Q.
      • Arora A.
      • Yang L.
      • Parelkar N.K.
      • Zhang G.
      • Liu X.
      • et al.
      Phosphorylation of AMPA receptors: Mechanisms and synaptic plasticity.
      ). Sutton et al. (
      • Sutton L.P.
      • Orlandi C.
      • Song C.
      • Oh W.C.
      • Muntean B.S.
      • Xie K.
      • et al.
      Orphan receptor GPR158 controls stress-induced depression.
      ) found that CRS upregulated the expression of orphan receptor GPR158 in the mPFC. GPR158 inhibited PKA-mediated phosphorylation of GluA1 at Ser845 and weakened excitatory synaptic strength. In contrast, GPR158 ablation led to a prominent antidepressant-like phenotype and promoted stress resilience (
      • Sutton L.P.
      • Orlandi C.
      • Song C.
      • Oh W.C.
      • Muntean B.S.
      • Xie K.
      • et al.
      Orphan receptor GPR158 controls stress-induced depression.
      ). In the BLA, chronic stress enhances cAMP-dependent PKA activity and increases GluA1 phosphorylation at Ser845, facilitating the synaptic insertion of GluA1 (
      • Yi E.S.
      • Oh S.
      • Lee J.K.
      • Leem Y.H.
      Chronic stress-induced dendritic reorganization and abundance of synaptosomal PKA-dependent CP-AMPA receptor in the basolateral amygdala in a mouse model of depression.
      ,
      • Kuniishi H.
      • Yamada D.
      • Wada K.
      • Yamada M.
      • Sekiguchi M.
      Stress induces insertion of calcium-permeable AMPA receptors in the OFC-BLA synapse and modulates emotional behaviours in mice.
      ). GluA1 Ser845 is also dephosphorylated by the calcium-dependent phosphatase calcineurin (also known as PP2B). PKA and PP2B are anchored at synapses by A-kinase-anchoring protein 150 (AKAP150) (the rodent ortholog of human AKAP79). Changes in the expression of AKAP79 protein are found in individuals with mood disorder (
      • Bernstein H.G.
      • Dobrowolny H.
      • Schott B.H.
      • Gorny X.
      • Becker V.
      • Steiner J.
      • et al.
      Increased density of AKAP5-expressing neurons in the anterior cingulate cortex of subjects with bipolar disorder.
      ). Recent evidence has shown that CRS facilitates the association of AKAP150 with PKA and increases GluA1 phosphorylation at Ser845 and surface insertion of GluA1 in the BLA, which contributes to depressive-like behaviors. Infusion of an interference peptide, Ht-31, which dissociates PKA from AKAP150, also displays antidepressant action (
      • Zhou H.Y.
      • He J.G.
      • Hu Z.L.
      • Xue S.G.
      • Xu J.F.
      • Cui Q.Q.
      • et al.
      A-kinase anchoring Protein 150 and protein kinase A complex in the basolateral amygdala contributes to depressive-like behaviors induced by chronic restraint stress.
      ). Phosphorylation of other synaptic proteins that directly interact with AMPARs are also involved in depression, such as TARP-γ8. Stress-induced CaMKIIβ upregulation in the lateral habenula mediates depressive-like behaviors through increasing the synaptic insertion of GluA1 (
      • Li K.
      • Zhou T.
      • Liao L.
      • Yang Z.
      • Wong C.
      • Henn F.
      • et al.
      βCaMKII in lateral habenula mediates core symptoms of depression.
      ). Long-term potentiation and memory formation are significantly impaired in mice lacking CaMKII phosphorylation sites of TARP-γ8 (
      • Park J.
      • Chávez A.E.
      • Mineur Y.S.
      • Morimoto-Tomita M.
      • Lutzu S.
      • Kim K.S.
      • et al.
      CaMKII phosphorylation of TARPγ-8 is a mediator of LTP and learning and memory.
      ). A recent study has demonstrated that CaMKIIβ-mediated TARP-γ8 phosphorylation enhances the expression of GluA1 in the hippocampus and promotes stress resilience (
      • Sakai Y.
      • Li H.
      • Inaba H.
      • Funayama Y.
      • Ishimori E.
      • Kawatake-Kuno A.
      • et al.
      Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway.
      ).
      Ubiquitination is a posttranslational process that attaches a single ubiquitin or polymeric ubiquitin chains to lysine residues of a substrate protein. It is shown that repeated stress impairs glutamatergic transmission in the PFC of juvenile male rats and causes cognitive impairment (
      • Yuen E.Y.
      • Wei J.
      • Liu W.
      • Zhong P.
      • Li X.
      • Yan Z.
      Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex.
      ). One of the underlying mechanisms involves glucocorticoid receptor–dependent transcriptional activation of E3 ubiquitin ligases Nedd4–1 and subsequent ubiquitination and degradation of AMPARs (
      • Yuen E.Y.
      • Wei J.
      • Liu W.
      • Zhong P.
      • Li X.
      • Yan Z.
      Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex.
      ,
      • Wei J.
      • Xiong Z.
      • Lee J.B.
      • Cheng J.
      • Duffney L.J.
      • Matas E.
      • Yan Z.
      Histone modification of Nedd4 ubiquitin ligase controls the loss of AMPA receptors and cognitive impairment induced by repeated stress.
      ). It is well known that AKAP150 is regulated by a ubiquitin-proteasome system that depends on synaptic activity (
      • Ehlers M.D.
      Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system.
      ). A recent study also found that hippocampal long-term depression induced AKAP150 degradation that was associated with the ubiquitination of AKAP150 (
      • Cheng W.
      • Siedlecki-Wullich D.
      • Català-Solsona J.
      • Fábregas C.
      • Fadó R.
      • Casals N.
      • et al.
      Proteasomal-mediated degradation of AKAP150 accompanies AMPAR endocytosis during cLTD.
      ).

      Summary and Future Directions

      In this review, we summarized the brain region– and subunit-specific changes in surface stability of AMPARs under stress condition in MDD. Chronic stress breaks the homeostasis of AMPAR trafficking via numerous molecules and signaling pathways, such as AMPAR auxiliary subunits, key AMPAR-interacting proteins, and posttranslational regulation of AMPARs. We proposed that normalization of AMPAR expression and function through bidirectional modulation of AMPARs would indirectly show antidepressant outcome (Figure 1).
      Figure thumbnail gr1
      Figure 1Dysfunction of AMPAR trafficking in depression. In the PFC and hippocampus, stress decreases AMPAR expression, which can be affected by the pathways including receptors (e.g., GPR158, GR, and mGluR5), neurotrophic factors (e.g., BDNF), cytokines (e.g., caspase-1 and IL-1β), transcriptional regulation (e.g., Dnmt3a, SMARCA3, and microRNA), posttranslational modifications (e.g., phosphorylation, ubiquitination), AMPAR-interacting proteins (e.g., homer1 and TARPγ-8) and mTORC1 signaling cascade. In the amygdala, stress enhances AMPAR-mediated synaptic transmission, which can be affected by the pathways including receptors (e.g., CRHR1 and D1R), posttranslational modifications (e.g., phosphorylation), AMPAR-interacting proteins (e.g., AKAP150), and endocannabinoids signaling cascade. Normalization of the abnormal synaptic AMPAR trafficking by genetic or pharmacological treatment represents antidepressant effect. 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; AEA, anandamide; AKAP150, A-kinase anchoring protein 150; AMPAR, AMPA receptor; Amy, amygdala; BDNF, brain-derived neurotrophic factor; CaMKIIβ, calcium/calmodulin-dependent protein kinase IIβ; CB1R, cannabinoid receptor type 1; COX2, cyclooxygenase-2; CRH, corticotropin-releasing hormone; D1R, dopamine 1 receptor; Dnm3a, DNA methyltransferase 3a; FAAH, fatty acid amide hydrolase; GPR158, G protein-coupled receptor 158; GR, glucocorticoid receptor; Hip, hippocampus; IL, interleukin; mGluR5, metabotropic glutamate receptor 5; mTOR, mechanistic target of rapamycin; mTORC1, mTOR complex 1; Nedd4, neuronal precursor cell-expressed developmentally downregulated 4; Nrsn2, neurensin 2; PDE4 phosphodiesterase-4; PFC, prefrontal cortex; PKA, protein kinase A; SMARCA3, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin 3; TARPγ8, transmembrane AMPAR regulatory proteins γ8.
      Nonselective NMDAR antagonists, such as ketamine, exert fast and long-lasting antidepressant-like effects; however, the psychomimetic effects limit their clinical application. Therefore, the downstream molecular and cellular mechanisms underlying the antidepressant actions of ketamine may hold great promise for antidepressant development. Ketamine is a racemic mixture of the enantiomers (R)-ketamine and (S)-ketamine. (S)-ketamine is an active isomer because of its higher affinity for NMDARs (Ki = 0.30 μM) and greater anesthetic potency than that of (R)-ketamine (Ki = 1.4 μM) (
      • Hashimoto K.
      Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine.
      ). However, preclinical findings reveal that (R)-ketamine exerts greater potency and longer-lasting antidepressant-like actions than (S)-ketamine and appears to have fewer behavioral side effects and less abuse liability (
      • Chang L.
      • Zhang K.
      • Pu Y.
      • Qu Y.
      • Wang S.M.
      • Xiong Z.
      • et al.
      Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine.
      ,
      • Fukumoto K.
      • Toki H.
      • Iijima M.
      • Hashihayata T.
      • Yamaguchi J.I.
      • Hashimoto K.
      • Chaki S.
      Antidepressant potential of (R)-ketamine in rodent models: Comparison with (S)-ketamine.
      ). Moreover, not all NMDAR antagonists exhibit rapid antidepressant efficacy. Notably, AZD6765, an NMDAR antagonist, shares several pharmacological profiles with (R,S)-ketamine at the NMDAR but does not show potent antidepressant-like effects (
      • Qu Y.
      • Yang C.
      • Ren Q.
      • Ma M.
      • Dong C.
      • Hashimoto K.
      Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model.
      ,
      • Sanacora G.
      • Johnson M.R.
      • Khan A.
      • Atkinson S.D.
      • Riesenberg R.R.
      • Schronen J.P.
      • et al.
      Adjunctive Lanicemine (AZD6765) in patients with major depressive disorder and history of inadequate response to antidepressants: A randomized, placebo-controlled study.
      ). Therefore, it is unlikely that the different antidepressant effects of the two ketamine enantiomers are related to the differences in their pharmacokinetic properties. Recently, the disinhibition hypothesis suggests that the rapid antidepressant effects of ketamine are mediated through blockade of NMDARs located on GABAergic (gamma-aminobutyric acidergic) interneurons. This in turn leads to a disinhibition of pyramidal cells in the PFC and an acute glutamate release (
      • Jelen L.A.
      • Young A.H.
      • Stone J.M.
      Ketamine: A tale of two enantiomers.
      ). The balance of neuronal activity in these regions is shifted toward excitatory transmission, which may underlie its antidepressant action. Indeed, ketamine exerts its antidepressant-like effects by initiating synaptogenesis in an AMPAR/BDNF (brain-derived neurotrophic factor)/mTOR complex 1–dependent manner, which involves recruitment of eukaryotic translation initiation factor 4E-BP2 and sustained increases in AMPAR expression (
      • Deyama S.
      • Duman R.S.
      Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine.
      ,
      • Duman R.S.
      • Deyama S.
      • Fogaça M.V.
      Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants.
      ).
      Despite this abundance of preclinical data regarding glutamatergic involvement in MDD, the results of subsequent clinical trials are dissatisfactory (
      • Kadriu B.
      • Musazzi L.
      • Johnston J.N.
      • Kalynchuk L.E.
      • Caruncho H.J.
      • Popoli M.
      • Zarate C.A.
      Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road.
      ). Despite promising antidepressant effects at the preclinical stage, several alternative NMDAR agents, including GluN2B-selective allosteric modulators (CP-101,606, CERC-301, and RO 25-RO6981) and glycine binding site modulators (AV-101 and rapastinel) failed to achieve the rapid and robust antidepressant efficacy of ketamine. In addition, several AMPAR-positive allosteric modulators, including ORG 26576 and CX1632, did not improve depressive symptoms significantly or meet trial end points in subsequent phase 2 clinical trials for MDD (
      • Nations K.R.
      • Dogterom P.
      • Bursi R.
      • Schipper J.
      • Greenwald S.
      • Zraket D.
      • et al.
      Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: An exploratory, randomized, double-blind, placebo-controlled trial.
      ,
      • Bernard K.
      • Gouttefangeas S.
      • Bretin S.
      • Galtier S.
      • Robert P.
      • Holthoff-Detto V.
      • et al.
      A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer’s disease and depressive symptoms.
      ).
      Moreover, no other glutamate modulators are currently approved for the treatment of depression worldwide. To date, major pharmaceutical efforts to develop novel antidepressant drugs directly target glutamate receptors. Although the strategy that directly targets the receptor has enabled the discovery of most drugs developed to modulate receptor signaling, obvious disadvantages still exist. First, glutamate receptors are widely distributed in the brain and fundamental to brain function. Meanwhile, stress induces brain region–specific bidirectional dysregulation of AMPAR-mediated synaptic transmission. Therefore, drugs that directly target the receptor lack specificity in the brain. Second, the use of an antagonist that directly blocks receptors is often accompanied with internalization and homeostatic regulation (
      • Changeux J.P.
      • Christopoulos A.
      Allosteric modulation as a unifying mechanism for receptor function and regulation.
      ). With the continuous progress of novel drugs, an innovative approach targeting receptor complexes has recently garnered great interest (
      • Maher M.P.
      • Matta J.A.
      • Gu S.
      • Seierstad M.
      • Bredt D.S.
      Getting a handle on neuropharmacology by targeting receptor-associated proteins.
      ,
      • Rosenbaum M.I.
      • Clemmensen L.S.
      • Bredt D.S.
      • Bettler B.
      • Strømgaard K.
      Targeting receptor complexes: A new dimension in drug discovery.
      ). AMPAR complexes consist of AMPAR subunits and receptor-associated proteins, which reveal relative spatiotemporal diversity of expression and have profound effects on the overall function and localization of receptors. Targeting AMPAR-associated proteins may provide a more selective pharmacology, increase the safety of depression treatment, and reduce side effects. As exemplified by the TARPγ-8 modulators LY3130481 and JNJ55511118, targeting AMPAR-associated proteins can provide brain region selectivity (
      • Kato A.S.
      • Burris K.D.
      • Gardinier K.M.
      • Gernert D.L.
      • Porter W.J.
      • Reel J.
      • et al.
      Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.
      ,
      • Dohrke J.N.
      • Watson J.F.
      • Birchall K.
      • Greger I.H.
      Characterizing the binding and function of TARP γ8-selective AMPA receptor modulators.
      ). The regional expression of TARPγ-8 explains why they preferentially block hippocampal and cortical AMPARs. TARPγ-8 in the hippocampus is required for the synaptic localization of CaMKIIβ-mediated GluA1 and subsequent stress resilience (
      • Sakai Y.
      • Li H.
      • Inaba H.
      • Funayama Y.
      • Ishimori E.
      • Kawatake-Kuno A.
      • et al.
      Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway.
      ). Further progress in AMPAR structural biology, especially by using cryoelectron microscopy approaches, will contribute to revealing the structure-guided medicinal chemistry of macromolecular receptor targets. Targeting AMPAR-associated proteins may be of value for the development of novel drugs for depression.

      Acknowledgments and Disclosures

      This work was supported by grants from the National Key R&D Program of China (Grant No. 2021ZD0202900 [to J-GC]), National Natural Science Foundation of China (Grant No. 82130110 [to J-GC] and Grant No. U21A20363 [to FW]), and Innovative Research Groups of National Natural Science Foundation of China (Grant No. 81721005 [to J-GC and FW]).
      The authors report no biomedical financial interests or potential conflicts of interest.

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