Control of Excitatory Synaptic Transmission by C-terminal Src Kinase

Xu, Jindong; Weerapura, Manjula; Ali, Mansoor; Jackson, Michael; Li, Hongbin; Liu, Gang; Xue, Song; Kwan, Chun L.; Manolson, Morris F.; Yang, Kai; MacDonald, John F.; Yu, Xian‐Min

doi:10.1074/jbc.m800917200

Cited by 34 publications

(64 citation statements)

References 44 publications

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“…2c). Thus, basal NMDAR synaptic responses were not affected by NRG1β-ErbB4 signaling, consistent with evidence that synaptic NMDARs are not tonically upregulated by Src in CA1 neurons 5,47,48 . Our findings indicate that NRG1β prevents and reverses the enhancement of synaptic NMDAR currents by Src but does not affect basal NMDAR function in CA1 neurons.…”

Section: Nrg1β-erbb4 Blocks Src Enhancement Of Nmdar Epscs In Ca1supporting

confidence: 63%

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

Pitcher

Kalia

et al. 2011

Nat Med

149

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: Nrg1β-erbb4 Blocks Src Enhancement Of Nmdar Epscs In Ca1supporting

confidence: 63%

“…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

149

146

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“…Src family kinases are likely mediators of NMDAR contributions to TrkB phosphorylation: they are concentrated in spines, engaged by NMDARs (19), and can effect TrkB transactivation (20). However, it is not known if brief episodes of TBS are sufficient to trigger synaptic Src signaling or if Src contributes to ligand-dependent TrkB activation.…”

Section: Resultsmentioning

confidence: 99%

Learning induces neurotrophin signaling at hippocampal synapses

Chen

Rex²,

Sanaiha³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Learning-induced trophic activity is thought to be critical for maintaining health of the aging brain. We report here that learning, acting through an unexpected pathway, activates synaptic receptors for one of the brain's primary trophic factors. Unsupervised learning, but not exploratory activity alone, robustly increased the number of postsynaptic densities associated with activated (phosphorylated) forms of BDNF's TrkB receptor in adult rat hippocampus; these increases were blocked by an NMDA receptor antagonist. Similarly, stimulation of hippocampal slices at the learning-related theta frequency increased synaptic TrkB phosphorylation in an NMDA receptor-dependent fashion. Theta burst stimulation, which was more effective in this regard than other stimulation patterns, preferentially engaged NMDA receptors that, in turn, activated Src kinases. Blocking the latter, or scavenging extracellular TrkB ligands, prevented theta-induced TrkB phosphorylation. Thus, synaptic TrkB activation was dependent upon both ligand presentation and postsynaptic signaling cascades. These results show that afferent activity patterns and cellular events involved in memory encoding initiate BDNF signaling through synaptic TrkB, thereby ensuring that learning will trigger neurotrophic support.BDNF | NMDA receptor | Src kinase | theta burst stimulation | TrkB E nvironmental enrichment and learning modify brain anatomy (1) and chemistry (2, 3) in older animals and slow cognitive decline and the onset of dementia in aged humans (4). Although multiple factors likely contribute to these effects, it is generally agreed that trophic factors play a central role. These releasable peptides stimulate growth and help maintain neuronal viability (5, 6) and are logical candidates for the agency whereby experience slows age-related deterioration of brain networks (7). However, there is little evidence that learning or learning-related patterns of electrical activity actually stimulate neurotrophic signaling at brain synapses. The absence of tests of the learning/ trophic signaling hypothesis is likely due to difficulties in sampling the activation state of proteins in the very small percentage of synapses affected by physiologically relevant patterns of activity or by learning itself (8, 9). Recent advances in restorative deconvolution microscopy have partly obviated these problems (8, 10). We used these techniques in the present studies to test the hypothesis that learning and learning-related brain rhythms cause the rapid activation of BDNF's TrkB receptor within synapses of the adult hippocampus.BDNF is of particular interest with regard to experience and aging because its expression by cortical neurons is both regulated by activity (11) and related to age-associated changes in brain anatomy and functioning (12). Accordingly, we focused on BDNF and asked if a 30 min period of a ubiquitous form of mammalian learning (i.e., unsupervised learning of a novel environment) increases the number of synapses containing the activated form of TrkB (13). W...

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“…The reversal of the decreased paw withdrawal threshold by Src40-49Tat several weeks after PNI likewise implies that there is an ongoing increase in Src activity relative to STEP, which is required to sustain pain hypersensitivity after PNI. Many candidate intracellular signaling pathways might cause the relative increase in Src activity within the NMDAR complex 16,38,39 that produces pain hypersensitivity, and it is conceivable these pathways may be common, or distinct, for inflammatory versus neuropathic pain.…”

Section: Within the Nmdar Complex Src Enhances Nmdar Function By Incmentioning

confidence: 99%

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

Liu

Gingrich

Vargas‐Caballero

et al. 2008

Nat Med

193

205

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Chronic pain hypersensitivity depends upon N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects from suppressing physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund's adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses, or cardiovascular, respiratory, locomotor or cognitive functions. Thus, by targeting Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.Chronic pain is categorized as inflammatory or neuropathic, each involving neuroplastic changes leading to hypersensitivity in peripheral and central nociceptive systems 1,2 . Multiple mechanisms including increased primary afferent excitability 3 , enhanced transmission in the dorsal horn 1 , changes in gene expression 4 , aberrant neuron-glia interactions 5,6 and neuronal apoptosis 7 are implicated in hypersensitivity in chronic pain models. Abundant pre-clinical evidence indicates that N-methyl-D-aspartate receptor (NMDARs) 8 are critically involved in pain hypersensitivity 9-11 . However, pharmacological blockade of these receptors in humans is deleterious because the activity of NMDARs is essential for many important physiological functions including breathing and locomotion 9,12,13 . A crucial signaling event for NMDAR-dependent neuroplasticity, including pain hypersensitivity 1,14 , is upregulation of NMDAR currents by mechanisms including relieving Mg 2+ blockade and receptor phosphorylation 15,16 . Thus, preferentially inhibiting mechanisms which upregulate NMDARs without affecting basal channel activity represents a strategy that may suppress pain hypersensitivity without impairing key physiological functions.

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Control of Excitatory Synaptic Transmission by C-terminal Src Kinase

Cited by 34 publications

References 44 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

Learning induces neurotrophin signaling at hippocampal synapses

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

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