P2X7受体在精神疾病中的研究进展
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摘要
P2X7受体属于ATP激活的非选择性阳离子通道型受体。P2X7受体在免疫细胞和神经系统中的胶质细胞中高表达,其通道开放可能与炎症反应、免疫应答和细胞调亡相关。研究发现,P2X7受体参与了多种精神疾病的发病机制,其机制涉及神经炎症发生、神经可塑性改变、细胞凋亡和神经递质释放异常等,提示该受体有望成为治疗精神疾病的新靶点,该文主要综述P2X7受体在抑郁症、双相情感障碍、精神分裂症和焦虑症这几类常见精神疾病中的研究进展。
The P2 X7 receptor is a trimeric adenosine triphosphate(ATP)-gated non-selective cation channel and is expressed predominantly in immune cells and glial cells in the nervous systems. Activation of P2 X7 channel is correlated with the inflammatory reactions, immune responses and cell apoptosis. Recently,it has been reported that the P2 X7 receptor contributes to the pathogenesis of various psychiatric disorders.The mechanisms may involve genesis of neuroinflammation, alteration of neural plasticity, cell apoptosis and abnormal releases of neurotransmitters in the nervous system. The studies indicate that the P2 X7 receptor could be a potential target of novel interventions of psychiatric disorders. This review summarizes recent progress of the P2 X7 receptor in several prevalent mental disorders, such as depression, bipolar disorder, schizophrenia and anxiety.
The P2 X7 receptor is a trimeric adenosine triphosphate(ATP)-gated non-selective cation channel and is expressed predominantly in immune cells and glial cells in the nervous systems. Activation of P2 X7 channel is correlated with the inflammatory reactions, immune responses and cell apoptosis. Recently,it has been reported that the P2 X7 receptor contributes to the pathogenesis of various psychiatric disorders.The mechanisms may involve genesis of neuroinflammation, alteration of neural plasticity, cell apoptosis and abnormal releases of neurotransmitters in the nervous system. The studies indicate that the P2 X7 receptor could be a potential target of novel interventions of psychiatric disorders. This review summarizes recent progress of the P2 X7 receptor in several prevalent mental disorders, such as depression, bipolar disorder, schizophrenia and anxiety.
引文
1 Di Virgilio F,Dal Ben D,Sarti AC,Giuliani AL,Falzoni S.The P2X7 receptor in infection and inflammation.Immunity 2017;47(1):15-31.
2 Czamara D,Muller-Myhsok B,Lucae S.The P2RX7 polymorphism rs2230912 is associated with depression:A meta-analysis.Prog Neuropsychopharmacol Biol Psychiatry 2018;82272-7.
3 Illes P,Khan TM,Rubini P.Neuronal P2X7 receptors revisited:do they really exist?J Neurosci 2017;37(30):7049-62.
4 Metzger MW,Walser SM,Aprile-Garcia F,Dedic N,Chen A,Holsboer F,et al.Genetically dissecting P2rx7 expression within the central nervous system using conditional humanized mice.Purinergic Signal 2017;13(2):153-70.
5 Deuchars SA,Atkinson L,Brooke RE,Musa H,Milligan CJBatten TF,et al.Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems.JNeurosci 2001;21(18):7143-52.
6 Sperlagh B,Kofalvi A,Deuchars J,Atkinson L,Milligan CJ,Buckley NJ,et al.Involvement of P2X7 receptors in the regulation of neurotransmitter release in the rat hippocampus.J Neurochem 2002;81(6):1196-211.
7 Di Virgilio F,Schmalzing G,Markwardt F.The elusive P2X7macropore.Trends Cell Biol 2018;28(5):392-404.
8 Giuliani AL,Sar ti AC,Falzoni S,Di Virgilio F.The P2X7receptor-interleukin-1 liaison.Front Pharmacol 2017;8:123.
9 Adinolfi E,Giuliani AL,De Marchi E,Pegoraro A,Orioli E,Di Virgilio F.The P2X7 receptor:A main player in inflammation.Biochem Pharmacol 2018;151:234-44.
10 Barbera-Cremades M,Gomez AI,Baroja-Mazo A,MartinezAlarcon L,Martinez CM,de Torre-Minguela C,et al.P2X7receptor induces tumor necrosis factor-alpha converting enzyme activation and release to boost TNF-alpha production ketamine alleviates depressive-like behaviors via down-regulating inflammatory cytokines induced by chronic restraint stress in mice.Front Immunol 2017;8(8):862.
11 Csolle C,Baranyi M,Zsilla G,Kittel A,Goloncser F,Illes P,et al.Neurochemical Changes in the mouse hippocampus underlying the antidepressant effect of genetic deletion of P2X7 receptors.PLoS One 2013;8(6):e66547.
12 Barros-Barbosa AR,Lobo MG,Ferreirinha F,Correia-de-Sa P,Cordeiro JM.P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes.Neuroscience 2015;306:74-90.
13 Otrokocsi L,Kittel A,Sperlagh B.P2X7 receptors drive spine synapse plasticity in the learned helplessness model of depression.Int J Neuropsychopharmacol 2017;20(10):813-22.
14 Pelegrin P,Surprenant A.Pannexin-1 couples to maitotoxin-and nigericin-induced interleukin-1beta release through a dye uptakeindependent pathway.J Biol Chem 2007;282(4):2386-94.
15 Burnstock G.Purinergic signalling:therapeutic developments Front Pharmacol 2017;8:661.
16 Aprile-Garcia F,Metzger MW,Paez-Pereda M,Stadler H,Acuna M,Liberman AC,et al.Co-expression of wild-type P2X7R with Gln460Arg variant alters receptor function.PLoS One 2016;11(3):e0151862.
17 Backlund L,Lavebratt C,Frisen L,Nikamo P,Hukic Sudic DTraskman-Bendz L,et al.P2RX7:expression responds to sleep deprivation and associates with rapid cycling in bipolar disorder type 1.PLoS One 2012;7(8):e43057.
18 Boucher AA,Arnold JC,Hunt GE,Spiro A,Spencer J,Brown C,et al.Resilience and reduced c-Fos expression in P2X7receptor knockout mice exposed to repeated forced swim test.Neuroscience 2011;189:170-7.
19 Csolle C,Ando RD,Kittel A,Goloncser F,Baranyi M,Soproni K,et al.The absence of P2X7 receptors(P2rx7)on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice.Int J Neuropsychopharmacol 2013;16(1):213-33.
20 Wilkinson SM,Gunosewoyo H,Barron ML,Boucher A,McDonnell M,Turner P,et al.The first CNS-active carborane:Anovel P2X7 receptor antagonist with antidepressant activity.ACSChem Neurosci 2014;5(5):335-9.
21 Basso AM,Bratcher NA,Harris RR,Jarvis MF,Decker MWRueter LE.Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety:relevance for neuropsychiatric disorders.Behav Brain Res 2009;198(1):83-90.
22 Yue N,Huang H,Zhu X,Han Q,Wang Y,Li B,et al.Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors.J Neuroinflammation 2017;14(1):102.
23 Wetsman N.Inflammatory illness:Why the next wave of antidepressants may target the immune system.Nat Med 2017;23(9):1009-11.
24 Jones KA,Thomsen C.The role of the innate immune system in psychiatric disorders.Mol Cell Neurosci 2013;5:352-62.
25 Corwin EJ,Johnston N,Pugh L.Symptoms of postpartum depression associated with elevated levels of interleukin-1 beta during the first month postpartum.Biol Res Nurs 2008;10(2):128-33.
26 Diniz BS,Teixeira AL,Talib L,Gattaz WF,Forlenza OV.Interleukin-1beta serum levels is increased in antidepressant-free elderly depressed patients.Am J Geriatr Psychiatry 2010;18(2):172-6.
27 Mingam R,De Smedt V,Amedee T,Bluthe RM,Kelley KW,Dantzer R,et al.In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1 beta in the murine brain Brain Behav Immun 2008;22(2):234-44.
28 Albalawi F,Lu W,Beckel JM,Lim JC,McCaughey SA,Mitchell CH.The P2X7 receptor primes IL-1beta and the NLRP3inflammasome in astrocytes exposed to mechanical strain.Front Cell Neurosci 2017;11227.
29 Murphy N,Lynch MA.Activation of the P2X(7)receptor induces migration of glial cells by inducing cathepsin B degradation of tissue inhibitor of metalloproteinase 1.J Neurochem 2012;123(5):761-70.
30 Huang Y,Coupland NJ,Lebel RM,Carter R,Seres P,Wilman AH,et al.Structural changes in hippocampal subfields in major depressive disorder:a high-field magnetic resonance imaging study.Biol Psychiatry 2013;74(1):62-8.
31 Kang HJ,Voleti B,Hajszan T,Rajkowska G,Stockmeier CA,Licznerski P,et al.Decreased expression of synapse-related genes and loss of synapses in major depressive disorder.Nat Med2012;18(9):1413-7.
32 Gerhard DM,Wohleb ES,Duman RS.Emerging treatment mechanisms for depression:focus on glutamate and synaptic plasticity.Drug Discov Today 2016;21(3):454-64.
33 Hajszan T,Dow A,Warner-Schmidt JL,Szigeti-Buck K,Sallam NL,Parducz A,et al.Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression.Biol Psychiatry 2009;65(5):392-400.
34 Serra MP,Poddighe L,Boi M,Sanna F,Piludu MA,Corda MGet al.Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability(Roman low-avoidance)and resistance(Roman high-avoidance)to stress-induced depression.Brain Behav 2017;7(10):e00861.
35 Papp L,Vizi ES,Sperlagh B.Lack of ATP-evoked GABA and glutamate release in the hippocampus of P2X7 receptor-/-mice.Neuroreport 2004;15(15):2387-91.
36 Dwivedi Y.Brain-derived neurotrophic factor:role in depression and suicide.Neuropsychiatr Dis Treat 2009;5:433-49.
37 Karege F,Schwald M,Cisse M.Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets Neurosci Lett 2002;328(3):261-4.
38 Goloncser F,Baranyi M,Balazsfi D,Demeter K,Haller J,Freund TFF,et al.Regulation of hippocampal 5-HT release by P2X7receptors in response to optogenetic stimulation of median raphe terminals of mice.Front Mol Neurosci 2017;10325.
39 Ashman SB,Monk TH,Kupfer DJ,Clark CH,Myers FS,Frank Eet al.Relationship between social rhythms and mood in patients with rapid cycling bipolar disorder.Psychiatry Res 1999;86(1):1-8.
40 Duan S,Anderson CM,Keung EC,Chen Y,Chen Y,Swanson RA.P2X7 receptor-mediated release of excitatory amino acids from astrocytes.J Neurosci 2003;23(4):1320-8.
41 Monif M,Burnstock G,Williams DA.Microglia:proliferation and activation driven by the P2X7 receptor.Int J Biochem Cell Biol 2010;42(11):1753-6.
42 O’Brien SM,Scully P,Scott LV,Dinan TG.Cytokine profiles in bipolar affective disorder:focus on acutely ill patients.J Affect Disord 2006;90(2-3):263-7.
43 Soderlund J,Olsson SK,Samuelsson M,Walther-Jallow LJohansson C,Erhardt S,et al.Elevation of cerebrospinal fluid interleukin-1ss in bipolar disorder.J Psychiatry Neurosci 2011;36(2):114-8.
44 Gubert C,Fries GR,Pfaffenseller B,Ferrari P,Coutinho-Silva RMorrone FB,et al.Role of P2X7 receptor in an animal model of mania induced by D-Amphetamine.Mol Neurobiol 2016;53(1):611-20.
45 Kovanyi B,Csolle C,Calovi S,Hanuska A,Kato E,Koles L,et al.The role of P2X7 receptors in a rodent PCP-induced schizophrenia model.Sci Rep 2016;6:36680.
46 Lewis DA,Sweet RA.Schizophrenia from a neural circuitry perspective:advancing toward rational pharmacological therapies.J Clin Invest 2009;119(4):706-16.
47 Geddes AE,Huang XF,Newell KA.Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1and their role in schizophrenia.Prog Neuropsychopharmacol Biol Psychiatry 2011;35(4):896-904.
48 Erhardt A,Lucae S,Unschuld PG,Ising M,Kern N,Salyakina D,et al.Association of polymorphisms in P2RX7 and CaMKKb with anxiety disorders.J Affect Disord 2007;101(1-3):159-68.
49 Xie B,Chen Y,Zhang S,Wu X,Zhang Z,Peng Y,et al.The expression of P2X7 receptors on peripheral blood mononuclear cells in patients with primary Sjogren’s syndrome and its correlation with anxiety and depression.Clin Exp Rheumatol2014;32(3):354-60.
50 Iwata M,Ota K T,Li XY,Sakaue F,Li N,Dutheil S,et al.Psychological Stress Activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type2X7 receptor.Biol Psychiatry 2016;80(1):12-22.
2 Czamara D,Muller-Myhsok B,Lucae S.The P2RX7 polymorphism rs2230912 is associated with depression:A meta-analysis.Prog Neuropsychopharmacol Biol Psychiatry 2018;82272-7.
3 Illes P,Khan TM,Rubini P.Neuronal P2X7 receptors revisited:do they really exist?J Neurosci 2017;37(30):7049-62.
4 Metzger MW,Walser SM,Aprile-Garcia F,Dedic N,Chen A,Holsboer F,et al.Genetically dissecting P2rx7 expression within the central nervous system using conditional humanized mice.Purinergic Signal 2017;13(2):153-70.
5 Deuchars SA,Atkinson L,Brooke RE,Musa H,Milligan CJBatten TF,et al.Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems.JNeurosci 2001;21(18):7143-52.
6 Sperlagh B,Kofalvi A,Deuchars J,Atkinson L,Milligan CJ,Buckley NJ,et al.Involvement of P2X7 receptors in the regulation of neurotransmitter release in the rat hippocampus.J Neurochem 2002;81(6):1196-211.
7 Di Virgilio F,Schmalzing G,Markwardt F.The elusive P2X7macropore.Trends Cell Biol 2018;28(5):392-404.
8 Giuliani AL,Sar ti AC,Falzoni S,Di Virgilio F.The P2X7receptor-interleukin-1 liaison.Front Pharmacol 2017;8:123.
9 Adinolfi E,Giuliani AL,De Marchi E,Pegoraro A,Orioli E,Di Virgilio F.The P2X7 receptor:A main player in inflammation.Biochem Pharmacol 2018;151:234-44.
10 Barbera-Cremades M,Gomez AI,Baroja-Mazo A,MartinezAlarcon L,Martinez CM,de Torre-Minguela C,et al.P2X7receptor induces tumor necrosis factor-alpha converting enzyme activation and release to boost TNF-alpha production ketamine alleviates depressive-like behaviors via down-regulating inflammatory cytokines induced by chronic restraint stress in mice.Front Immunol 2017;8(8):862.
11 Csolle C,Baranyi M,Zsilla G,Kittel A,Goloncser F,Illes P,et al.Neurochemical Changes in the mouse hippocampus underlying the antidepressant effect of genetic deletion of P2X7 receptors.PLoS One 2013;8(6):e66547.
12 Barros-Barbosa AR,Lobo MG,Ferreirinha F,Correia-de-Sa P,Cordeiro JM.P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes.Neuroscience 2015;306:74-90.
13 Otrokocsi L,Kittel A,Sperlagh B.P2X7 receptors drive spine synapse plasticity in the learned helplessness model of depression.Int J Neuropsychopharmacol 2017;20(10):813-22.
14 Pelegrin P,Surprenant A.Pannexin-1 couples to maitotoxin-and nigericin-induced interleukin-1beta release through a dye uptakeindependent pathway.J Biol Chem 2007;282(4):2386-94.
15 Burnstock G.Purinergic signalling:therapeutic developments Front Pharmacol 2017;8:661.
16 Aprile-Garcia F,Metzger MW,Paez-Pereda M,Stadler H,Acuna M,Liberman AC,et al.Co-expression of wild-type P2X7R with Gln460Arg variant alters receptor function.PLoS One 2016;11(3):e0151862.
17 Backlund L,Lavebratt C,Frisen L,Nikamo P,Hukic Sudic DTraskman-Bendz L,et al.P2RX7:expression responds to sleep deprivation and associates with rapid cycling in bipolar disorder type 1.PLoS One 2012;7(8):e43057.
18 Boucher AA,Arnold JC,Hunt GE,Spiro A,Spencer J,Brown C,et al.Resilience and reduced c-Fos expression in P2X7receptor knockout mice exposed to repeated forced swim test.Neuroscience 2011;189:170-7.
19 Csolle C,Ando RD,Kittel A,Goloncser F,Baranyi M,Soproni K,et al.The absence of P2X7 receptors(P2rx7)on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice.Int J Neuropsychopharmacol 2013;16(1):213-33.
20 Wilkinson SM,Gunosewoyo H,Barron ML,Boucher A,McDonnell M,Turner P,et al.The first CNS-active carborane:Anovel P2X7 receptor antagonist with antidepressant activity.ACSChem Neurosci 2014;5(5):335-9.
21 Basso AM,Bratcher NA,Harris RR,Jarvis MF,Decker MWRueter LE.Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety:relevance for neuropsychiatric disorders.Behav Brain Res 2009;198(1):83-90.
22 Yue N,Huang H,Zhu X,Han Q,Wang Y,Li B,et al.Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors.J Neuroinflammation 2017;14(1):102.
23 Wetsman N.Inflammatory illness:Why the next wave of antidepressants may target the immune system.Nat Med 2017;23(9):1009-11.
24 Jones KA,Thomsen C.The role of the innate immune system in psychiatric disorders.Mol Cell Neurosci 2013;5:352-62.
25 Corwin EJ,Johnston N,Pugh L.Symptoms of postpartum depression associated with elevated levels of interleukin-1 beta during the first month postpartum.Biol Res Nurs 2008;10(2):128-33.
26 Diniz BS,Teixeira AL,Talib L,Gattaz WF,Forlenza OV.Interleukin-1beta serum levels is increased in antidepressant-free elderly depressed patients.Am J Geriatr Psychiatry 2010;18(2):172-6.
27 Mingam R,De Smedt V,Amedee T,Bluthe RM,Kelley KW,Dantzer R,et al.In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1 beta in the murine brain Brain Behav Immun 2008;22(2):234-44.
28 Albalawi F,Lu W,Beckel JM,Lim JC,McCaughey SA,Mitchell CH.The P2X7 receptor primes IL-1beta and the NLRP3inflammasome in astrocytes exposed to mechanical strain.Front Cell Neurosci 2017;11227.
29 Murphy N,Lynch MA.Activation of the P2X(7)receptor induces migration of glial cells by inducing cathepsin B degradation of tissue inhibitor of metalloproteinase 1.J Neurochem 2012;123(5):761-70.
30 Huang Y,Coupland NJ,Lebel RM,Carter R,Seres P,Wilman AH,et al.Structural changes in hippocampal subfields in major depressive disorder:a high-field magnetic resonance imaging study.Biol Psychiatry 2013;74(1):62-8.
31 Kang HJ,Voleti B,Hajszan T,Rajkowska G,Stockmeier CA,Licznerski P,et al.Decreased expression of synapse-related genes and loss of synapses in major depressive disorder.Nat Med2012;18(9):1413-7.
32 Gerhard DM,Wohleb ES,Duman RS.Emerging treatment mechanisms for depression:focus on glutamate and synaptic plasticity.Drug Discov Today 2016;21(3):454-64.
33 Hajszan T,Dow A,Warner-Schmidt JL,Szigeti-Buck K,Sallam NL,Parducz A,et al.Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression.Biol Psychiatry 2009;65(5):392-400.
34 Serra MP,Poddighe L,Boi M,Sanna F,Piludu MA,Corda MGet al.Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability(Roman low-avoidance)and resistance(Roman high-avoidance)to stress-induced depression.Brain Behav 2017;7(10):e00861.
35 Papp L,Vizi ES,Sperlagh B.Lack of ATP-evoked GABA and glutamate release in the hippocampus of P2X7 receptor-/-mice.Neuroreport 2004;15(15):2387-91.
36 Dwivedi Y.Brain-derived neurotrophic factor:role in depression and suicide.Neuropsychiatr Dis Treat 2009;5:433-49.
37 Karege F,Schwald M,Cisse M.Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets Neurosci Lett 2002;328(3):261-4.
38 Goloncser F,Baranyi M,Balazsfi D,Demeter K,Haller J,Freund TFF,et al.Regulation of hippocampal 5-HT release by P2X7receptors in response to optogenetic stimulation of median raphe terminals of mice.Front Mol Neurosci 2017;10325.
39 Ashman SB,Monk TH,Kupfer DJ,Clark CH,Myers FS,Frank Eet al.Relationship between social rhythms and mood in patients with rapid cycling bipolar disorder.Psychiatry Res 1999;86(1):1-8.
40 Duan S,Anderson CM,Keung EC,Chen Y,Chen Y,Swanson RA.P2X7 receptor-mediated release of excitatory amino acids from astrocytes.J Neurosci 2003;23(4):1320-8.
41 Monif M,Burnstock G,Williams DA.Microglia:proliferation and activation driven by the P2X7 receptor.Int J Biochem Cell Biol 2010;42(11):1753-6.
42 O’Brien SM,Scully P,Scott LV,Dinan TG.Cytokine profiles in bipolar affective disorder:focus on acutely ill patients.J Affect Disord 2006;90(2-3):263-7.
43 Soderlund J,Olsson SK,Samuelsson M,Walther-Jallow LJohansson C,Erhardt S,et al.Elevation of cerebrospinal fluid interleukin-1ss in bipolar disorder.J Psychiatry Neurosci 2011;36(2):114-8.
44 Gubert C,Fries GR,Pfaffenseller B,Ferrari P,Coutinho-Silva RMorrone FB,et al.Role of P2X7 receptor in an animal model of mania induced by D-Amphetamine.Mol Neurobiol 2016;53(1):611-20.
45 Kovanyi B,Csolle C,Calovi S,Hanuska A,Kato E,Koles L,et al.The role of P2X7 receptors in a rodent PCP-induced schizophrenia model.Sci Rep 2016;6:36680.
46 Lewis DA,Sweet RA.Schizophrenia from a neural circuitry perspective:advancing toward rational pharmacological therapies.J Clin Invest 2009;119(4):706-16.
47 Geddes AE,Huang XF,Newell KA.Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1and their role in schizophrenia.Prog Neuropsychopharmacol Biol Psychiatry 2011;35(4):896-904.
48 Erhardt A,Lucae S,Unschuld PG,Ising M,Kern N,Salyakina D,et al.Association of polymorphisms in P2RX7 and CaMKKb with anxiety disorders.J Affect Disord 2007;101(1-3):159-68.
49 Xie B,Chen Y,Zhang S,Wu X,Zhang Z,Peng Y,et al.The expression of P2X7 receptors on peripheral blood mononuclear cells in patients with primary Sjogren’s syndrome and its correlation with anxiety and depression.Clin Exp Rheumatol2014;32(3):354-60.
50 Iwata M,Ota K T,Li XY,Sakaue F,Li N,Dutheil S,et al.Psychological Stress Activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type2X7 receptor.Biol Psychiatry 2016;80(1):12-22.