First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients

Pilowsky, Lyn S.; Bressan, Rodrigo A.; Stone, James; Erlandsson, Kjell; Mulligan, RS; Krystal, J.; Ell, PJ

doi:10.1038/sj.mp.4001751

Cited by 253 publications

(156 citation statements)

References 6 publications

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“…N-methyl-D-aspartate receptors have been implicated in the etiology and pathophysiology of schizophrenia, primarily because NMDA receptor antagonists produce schizophrenia-like symptoms in healthy individuals (Honey et al 2005;Javitt and Zukin 1991;Krystal et al 1994;Luby et al 1959;Malhotra et al 1996;Newcomer et al 1999;Olney and Farber 1995) and exacerbate preexisting symptoms in individuals with schizophrenia (Lahti et al 1995;Malhotra et al 1997). Postmortem and genetic linkage studies (Harrison and Weinberger 2005;Kristiansen et al 2006;Moghaddam 2003), as well as a preliminary imaging study (Pilowsky et al 2006), also support a role for NMDA receptor dysfunction in schizophrenia. N-methyl-Daspartate receptor antagonists such as dizocilpine (MK801), phencyclidine (PCP), or low doses of ketamine are routinely used in preclinical studies to model schizophrenia.…”

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confidence: 93%

Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

Lecourtier

Homayoun

Tamagnan

et al. 2007

Biological Psychiatry

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Background-Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptor hypofunction may be associated with schizophrenia. Activation of metabotropic glutamate 5 (mGlu5) receptors enhances NMDA receptor mediated currents in vitro, implying that allosteric modulation of mGlu5 receptors may have therapeutic efficacy for schizophrenia. The aim of this study was to determine if positive allosteric modulators of mGlu5 receptors are effective in reversing two cellular effects of NMDA receptor antagonists that are relevant to schizophrenia: increases in corticolimbic dopamine neurotransmission and disruption of neuronal activity in the prefrontal cortex (PFC).

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confidence: 93%

Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

Lecourtier

Homayoun

Tamagnan

et al. 2007

Biological Psychiatry

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“…Consistent with a role for glutamate and NMDA receptors in expression of schizophrenia, D-serine, D-alanine and D-cycloserine, positive modulators of NMDA receptors show promise as adjuvant therapy for this disorder (15;16). Additionally, NMDA receptor deficits have been identified in vivo in medication-free schizophrenic patients (17) The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is widely distributed in the central and peripheral nervous systems at millimolar concentrations (18;19;20). NAAG is a mGluR3 selective group II mGluR agonist (21;22) and is codistributed with different small amine transmitters including glutamate and GABA (reviewed in 23; 24).…”

Section: Introductionmentioning

confidence: 99%

Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors

Olszewski

Wegorzewska

Monteiro

et al. 2008

Biological Psychiatry

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“…A key process regulating NMDAR activity is phosphorylation by NMDAR-associated kinases. Certain NMDAR-dependent functions, such as ventilation and locomotion, may be independent of NMDAR phosphorylation 4 , whereas phosphorylation-induced upregulation of NMDARs is critical for synaptic plasticity [5][6][7] .A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as hallucinations and cognitive deficits may be due to hypofunction of the NMDAR [8][9][10] . In support of this hypothesis, administering NMDAR-blocking drugs to otherwise normal adults elicits hallucinations and cognitive deficits 11 .…”

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confidence: 99%

“…A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as hallucinations and cognitive deficits may be due to hypofunction of the NMDAR [8][9][10] . In support of this hypothesis, administering NMDAR-blocking drugs to otherwise normal adults elicits hallucinations and cognitive deficits 11 .…”

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confidence: 99%

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Pitcher

Kalia

et al. 2011

Nat Med

152

146

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Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.Correspondence should be addressed to M.W.S. (mike.salter@utoronto.ca). 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Medicine website. AUTHOR CONTRIBUTIONSG.M.P. designed the project, conducted the hippocampal experiments, analyzed the data and wrote the manuscript. L.V.K. and D.N. carried out and analyzed biochemical experiments. E.K.L. oversaw and analyzed the prefrontal cortex experiments. N.M.G. carried out and analyzed the prefrontal cortex experiments. K.T.Y. maintained, housed and provided ErbB4 knockout mice. All authors participated in revising the manuscript and agreed to the final version. M.W.S. conceived the study, analyzed data, supervised the overall project and wrote the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. Nat Med. Author manuscript; available in PMC 2012 January 23. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptThe NMDAR, a major excitatory ligand-gated ion channel in the central nervous system and a principal mediator of synaptic plasticity, is a multiprotein complex whose core is a heterotetramer comprising two obligate GluN1 subunits and two GluN2(A-D) subunits 1,2 . Proteins associated with the core NMDAR have key roles in trafficking, stability, subunit composition and function of NMDARs 3 . A key process regulating NMDAR activity is phosphorylation by NMDAR-associated kinases. Certain NMDAR-dependent functions, such as ventilation and locomotion, may be independent of NMDAR phosphorylation 4 , whereas phosphorylation-induced upregulation of NMDARs is critical for synaptic plasticity [5][6][7] .A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as...

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First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients

Cited by 253 publications

References 6 publications

Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

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