Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada.
Nat Med. 2011 Apr;17(4):470-8. doi: 10.1038/nm.2315. Epub 2011 Mar 27.
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.
谷氨酸受体（NMDAR）的 N-甲基-D-天冬氨酸亚型功能低下被认为是精神分裂症患者认知功能障碍的一种机制。对于与精神分裂症相关的基因 NRG1 和 ERBB4，NMDAR 功能低下被认为是精神分裂症患者中发现的过度 NRG1-ErbB4 信号的关键有害后果。然而，我们在这里表明，神经调节蛋白 1β-ErbB4（NRG1β-ErbB4）信号不会导致 NMDAR 的普遍功能低下。相反，我们发现，在海马体和前额叶皮层中，NRG1β-ErbB4 信号抑制了非受体酪氨酸激酶Src 对突触 NMDAR 电流的增强作用。NRG1β-ErbB4 信号阻止了海马体 Schaffer 侧枝-CA1 突触的长时程增强诱导，并抑制了在 theta 爆发刺激期间 Src 依赖性的 NMDAR 反应增强。此外，NRG1β-ErbB4 信号通过抑制 Src 激酶活性来防止 theta 爆发诱导的 GluN2B 磷酸化。我们提出，NRG1-ErbB4 信号通过异常抑制 Src 介导的突触 NMDAR 功能增强，参与精神分裂症的认知功能障碍。
