Department of Molecular Neurobiology, Brain Research Institute and Center for Transdisciplinary Research, Niigata University, Niigata, 951-8585, Japan.
J Neurosci. 2011 Apr 13;31(15):5699-709. doi: 10.1523/JNEUROSCI.3477-10.2011.
Neuregulin-1 (NRG1) signaling is thought to contribute to both neuronal development and schizophrenia neuropathology. Here, we describe the developmental effects of excessive peripheral NRG1 signals on synaptic activity and AMPA receptor expression of GABAergic interneurons in postnatal rodent neocortex. A core peptide common to all NRG1 variants (eNRG1) was subcutaneously administered to mouse pups. Injected eNRG1 penetrated the blood-brain barrier and activated ErbB4 NRG1 receptors in the neocortex, in which ErbB4 mRNA is predominantly expressed by parvalbumin-positive GABAergic interneurons. We prepared neocortical slices from juvenile mice that were receiving eNRG1 subchronically and recorded inhibitory synaptic activity from layer V pyramidal neurons. Postnatal eNRG1 treatment significantly enhanced polysynaptic IPSCs, although monosynaptic IPSCs were not affected. Examination of excitatory inputs to parvalbumin-containing GABAergic interneurons revealed that eNRG1 treatment significantly increased AMPA-triggered inward currents and the amplitudes and frequencies of miniature EPSCs (mEPSCs). Similar effects on mEPSCs were observed in mice treated with a soluble, full-length form of NRG1 type I. Consistent with the electrophysiologic data, expression of the AMPA receptor GluA1 (i.e., GluR1, GluRA) was upregulated in the postsynaptic density/cytoskeletal fraction prepared from eNRG1-treated mouse neocortices. Cortical GABAergic neurons cultured with eNRG1 exhibited a significant increase in surface GluA1 immunoreactivity at putative synaptic sites on their dendrites. These results indicate that NRG1 circulating in the periphery influences postnatal development of synaptic AMPA receptor expression in cortical GABAergic interneurons and may play a role in conditions characterized by GABA-associated neuropathologic processes.
神经调节蛋白 1（NRG1）信号被认为有助于神经元发育和精神分裂症神经病理学。在这里，我们描述了过量外周 NRG1 信号对新生鼠大脑皮层 GABA 能中间神经元突触活性和 AMPA 受体表达的发育影响。所有 NRG1 变体共有的核心肽（eNRG1）被皮下给予小鼠幼仔。注射的 eNRG1 穿透血脑屏障并在大脑皮层中激活 ErbB4 NRG1 受体，其中 ErbB4 mRNA 主要由副甲状腺素阳性 GABA 能中间神经元表达。我们从小鼠制备新皮层切片，这些小鼠接受 eNRG1 亚慢性处理，并从第 V 层锥体神经元记录抑制性突触活性。出生后 eNRG1 处理显著增强了多突触 IPSC，尽管单突触 IPSC 不受影响。对含有副甲状腺素的 GABA 能中间神经元的兴奋性输入的检查表明，eNRG1 处理显著增加了 AMPA 触发的内向电流以及微小 EPSC（mEPSC）的幅度和频率。用 NRG1 类型 I 的可溶性全长形式处理的小鼠中也观察到了类似的 mEPSC 效应。与电生理数据一致，从接受 eNRG1 处理的小鼠新皮层制备的突触后密度/细胞骨架部分中，AMPA 受体 GluA1（即 GluR1、GluRA）的表达上调。与 eNRG1 共培养的皮层 GABA 能神经元在其树突上的假定突触部位表现出表面 GluA1 免疫反应性的显著增加。这些结果表明，外周循环的 NRG1 影响皮质 GABA 能中间神经元中突触 AMPA 受体表达的出生后发育，并可能在具有 GABA 相关神经病理过程的情况下发挥作用。
