Gain control of N-methyl-D-aspartate receptor activity by receptor-like protein tyrosine phosphatase alpha

Liu, Gang; Xue, Song; Chéry, Nadège; Liu, Qiang; Xu, Jindong; Kwan, Chun L.; Fu, Yang-Ping; Lu, Youming; Liu, Mingyao; Harder, Kenneth W.; Yu, Xian‐Min

doi:10.1093/emboj/cdf292

Cited by 73 publications

(90 citation statements)

References 48 publications

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“…Within the NMDAR complex, potential mediators of NRG1-ErbB4 signaling include the Src regulators Csk 48 and protein tyrosine phosphatase-α 58 . Another potential mediator is PSD-95, which suppresses Src activity in the NMDAR complex through binding of a sequence in the PSD-95 N-terminal region to the SH2 domain of Src 59 .…”

Section: Discussionmentioning

confidence: 99%

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

Pitcher

Kalia

et al. 2011

Nat Med

153

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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Section: Discussionmentioning

confidence: 99%

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

Pitcher

Kalia

et al. 2011

Nat Med

153

146

View full text Add to dashboard Cite

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“…4 A). In addition, based on the fact that Src, PSD-95, and NMDARs form a complex, and Src is activated after reelin application (Lei et al, 2002;Arnaud et al, 2003;Bock and Herz, 2003), we examined the level of Src that is associated with PSD-95 through immunoprecipitation with PSD-95 antibody followed by immunoblotting with Src antibody. Reelin treatment significantly increases the amount of Src that is associated with PSD-95 protein by approximately threefold (Fig.…”

Section: Reelin Signaling Leads To Src-dependent Phosphorylation Of Nmentioning

confidence: 99%

Differential Reelin-Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus

Qiu¹,

Zhao²,

Korwek³

et al. 2006

J. Neurosci.

166

161

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The developmental lamination of the hippocampus and other cortical structures requires a signaling cascade initiated by reelin and its receptors, apoER2 (apolipoprotein E receptor 2) and VLDLR (very-low-density lipoprotein receptor). However, the functional significance of continued reelin expression in the postnatal brain remains poorly understood. Here, we show that reelin application to adult mice hippocampal slices leads to enhanced glutamatergic transmission mediated by NMDA receptors (NMDARs) and AMPA receptors (AMPARs) through distinct mechanisms. Application of recombinant reelin enhanced NMDAR-mediated currents through postsynaptic mechanisms, as revealed by the variance-mean analysis of synaptic NMDAR currents, assessment of spontaneous miniature events, and the levels of NMDAR subunits at synaptic surface. In comparison, nonstationary fluctuation analysis of miniature AMPAR currents and quantification of synaptic surface proteins revealed that reelin-induced enhancement of AMPAR responses was mediated by increased AMPAR numbers. Reelin enhancement of synaptic NMDAR currents was abolished when receptor-associated protein (RAP) or the Src inhibitor 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (PP1) was bath applied and was abrogated by includingPP1 in the recording electrodes. In comparison, including RAP or an inactive PP1 analog PP3 in the recording electrode was without effect. Interestingly, the increased AMPAR response after reelin application was not blocked by PP1 but was blocked by the phosphoinositide-3Ј kinase (PI3K) inhibitors wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride]. Furthermore, reelin-induced, PI3K-dependent AMPAR surface insertion was also observed in cultured hippocampal neurons. Together, these results reveal a differential functional coupling of reelin signaling with NMDAR and AMPAR function and define a novel mechanism for controlling synaptic strength and plasticity in the adult hippocampus.

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“…The activation of Ptpra, which binds to the PSD-95/Discs large/zona occludens-1 (PDZ) domain of PSD-95, enhances NMDA receptor-mediated synaptic responses, and the blockade of endogenous Ptpra results in impairment of the induction of hippocampal LTP (Lei et al, 2002). Mutant mice lacking Ptpra also exhibit impaired LTP (Petrone et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, properties of the NMDA receptor, which is essential for the induction of LTP in the hippocampal CA1 region (Nicoll and Malenka, 1995), are dynamically regulated by Src family tyrosine kinases (Wang and Salter, 1994;Manabe et al, 2000;Nakazawa et al, 2001;Salter and Kalia, 2004). On the other hand, mice deficient in some protein tyrosine phosphatases (PTPs) show different phenotypes in LTP and learning (Uetani et al, 2000;Lei et al, 2002;Petrone et al, 2003). Thus, the regulation of synaptic plasticity through PTPs is rather complex, and the precise roles of PTPs still remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Age-Dependent Enhancement of Hippocampal Long-Term Potentiation and Impairment of Spatial Learning through the Rho-Associated Kinase Pathway in Protein Tyrosine Phosphatase Receptor Type Z-Deficient Mice

Niisato

Fujikawa²,

Komai³

et al. 2005

J. Neurosci.

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Although protein tyrosine phosphatases (PTPs) are expressed abundantly in the brain, their roles in synaptic plasticity have not been well elucidated. In this study, we have examined the physiological functions of Ptprz, which is a receptor-type PTP expressed predominantly in the brain as a chondroitin sulfate proteoglycan. We have examined phenotypes of mutant mice deficient in Ptprz using electrophysiological, pharmacological, and behavioral approaches. Mutant mice exhibit enhanced long-term potentiation (LTP) in the CA1 region of hippocampal slices and impaired spatial learning abilities in an age-dependent manner: young adult (Ͻ10 weeks old) mutant mice show normal LTP and learning abilities in the Morris water maze task, whereas adult (Ͼ13 weeks old) mutant mice exhibit enhanced LTP and impairment in the task. The enhanced LTP is specifically canceled out by pharmacological inhibition of Rho-associated kinase (ROCK), a major downstream effector of Rho. These findings suggest that the lack of Ptprz leads to aberrant activation of ROCK and resultantly to enhanced LTP in the slice and learning impairments in the animal.

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Gain control of N-methyl-D-aspartate receptor activity by receptor-like protein tyrosine phosphatase alpha

Cited by 73 publications

References 48 publications

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

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

Differential Reelin-Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus

Age-Dependent Enhancement of Hippocampal Long-Term Potentiation and Impairment of Spatial Learning through the Rho-Associated Kinase Pathway in Protein Tyrosine Phosphatase Receptor Type Z-Deficient Mice

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