Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors
Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors
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DOI：
10.1038/nm.2315
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发表时间：
2011-04-01
期刊：
影响因子：
82.9
通讯作者：
Salter, Michael W.
中科院分区：
文献类型：
--
作者：
Pitcher, Graham M.;Kalia, Lorraine V.;Salter, Michael W.
谷氨酸受体的N-甲基-D-天冬氨酸亚型（NMDAR）功能减退被假设为精神分裂症患者认知功能障碍的潜在机制。因此，对于精神分裂症相关基因NRG 1和ERBB 4，NMDAR功能低下被认为是精神分裂症患者中发现的过度NRG 1-ErbB 4信号传导的关键有害后果。然而，我们在这里表明神经调节素1 β-ErbB 4（NRG 1 β-ErbB 4）信号传导不会导致NMDAR的一般功能减退。相反，我们发现，在海马和前额皮质，NRG 1 β-ErbB 4信号抑制非受体酪氨酸激酶Src的突触NMDAR电流的增强。NRG 1 β-ErbB 4信号传导阻止了海马Schaffer侧支-CA 1突触长时程增强的诱导，并抑制了θ-爆发刺激期间NMDAR反应的Src依赖性增强。此外，NRG 1 β-ErbB 4信号通过抑制Src激酶活性阻止θ爆发诱导的GluN 2B磷酸化。我们认为NRG 1-ErbB 4信号通过异常抑制Src介导的突触NMDAR功能增强参与精神分裂症认知功能障碍。
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 1 beta-ErbB4 (NRG1 beta-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1 beta-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1 beta-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, NRG1 beta-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.