ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation
ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation
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DOI：
10.1073/pnas.1010669107
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Gao, Tian-Ming
中科院分区：
文献类型：
--
作者：
Chen, Yong-Jun;Zhang, Meng;Gao, Tian-Ming
神经调节蛋白1（NRG 1）是一种通过刺激ErbB受体酪氨酸激酶起作用的营养因子，并且与神经发育和突触可塑性有关。在这项研究中，我们探讨了其抑制海马长时程增强（LTP）的机制。我们发现，NRG 1并不改变SC-CA 1突触的突触能传递，但通过突触前机制增加CA 1锥体细胞GABA（A）受体介导的突触电流。抑制GABA（A）受体可阻断NRG 1对LTP的抑制作用，并阻止外ErbB 4增强LTP，提示GABA能传递的作用。为了进一步验证这一假设，我们产生了小清蛋白（PV）-Cre; ErbB 4（-/-）小鼠，其中ErbB 4，一种脑中的NRG 1受体，在PV阳性中间神经元中特异性消融。NRG 1不再能够增加PV-Cre; ErbB 4（-/-）海马的抑制性突触后电流和抑制LTP。因此，PV-Cre; ErbB 4（-/-）小鼠的情境恐惧条件反射（一种依赖于海马区的测试）受损。与此相反，在锥体神经元中的ErbB 4的消融对海马LTP或上下文恐惧条件反射的NRG 1调节没有影响。这些结果表明，在PV阳性的中间神经元，但不是在锥体神经元的突触可塑性的ErbB 4的关键作用，并支持NRG 1抑制LTP通过增强GABA的释放的工作模型。考虑到NRG 1和ErbB 4是精神分裂症的易感基因，这些观察有助于更好地理解NRG 1/ErbB 4信号异常如何参与精神分裂症的发病机制。
Neuregulin 1 (NRG1) is a trophic factor that acts by stimulating ErbB receptor tyrosine kinases and has been implicated in neural development and synaptic plasticity. In this study, we investigated mechanisms of its suppression of long-term potentiation (LTP) in the hippocampus. We found that NRG1 did not alter glutamatergic transmission at SC-CA1 synapses but increased the GABA(A) receptor-mediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABA(A) receptors blocked the suppressing effect of NRG1 on LTP and prevented ecto-ErbB4 from enhancing LTP, implicating a role of GABAergic transmission. To test this hypothesis further, we generated parvalbumin (PV)-Cre; ErbB4(-/-) mice in which ErbB4, an NRG1 receptor in the brain, is ablated specifically in PV-positive interneurons. NRG1 was no longer able to increase inhibitory postsynaptic currents and to suppress LTP in PV-Cre; ErbB4(-/-) hippocampus. Accordingly, contextual fear conditioning, a hippocampus-dependent test, was impaired in PV-Cre;ErbB4(-/-) mice. In contrast, ablation of ErbB4 in pyramidal neurons had no effect on NRG1 regulation of hippocampal LTP or contextual fear conditioning. These results demonstrate a critical role of ErbB4 in PV-positive interneurons but not in pyramidal neurons in synaptic plasticity and support a working model that NRG1 suppresses LTP by enhancing GABA release. Considering that NRG1 and ErbB4 are susceptibility genes of schizophrenia, these observations contribute to a better understanding of how abnormal NRG1/ErbB4 signaling may be involved in the pathogenesis of schizophrenia.