National Institutes of Health, Eunice Shriver Kennedy NICHD, Section on Molecular Neurobiology, Bethesda, Maryland 20892-3714, USA.
Hippocampus. 2010 Jun;20(6):724-44. doi: 10.1002/hipo.20675.
Neuregulins (NRGs) are ligands of ErbB receptor tyrosine kinases. The NRG1-ErbB4 pathway has been shown to modulate hippocampal synaptic plasticity and network oscillations in the adult rodent brain. To identify cells that mediate these effects, here we determine the expression pattern of ErbB4 in four functionally distinct classes of interneurons that represent the majority of all inhibitory neurons in the adult hippocampus. On the basis of data from nine mice and 25,000 cells, we show that ErbB4 is expressed in cells that are positive for cholecystokinin (CCK, 54%), parvalbumin (PV, 42%), or neuronal nitric oxide synthase (nNOS, 39%) in a layer-specific and region-specific manner, whereas cells expressing somatostatin (SOM) are rarely immunoreactive for ErbB4 (1%). We next compared the numerical density (cells/mm(3)) and the distribution of interneurons between ErbB4-/- mice and wildtype controls. Based on data from 25 mice and 56,000 cells, we detected reductions of PV-positive and nNOS-positive cells in knockouts (-24% and -27%, respectively) but only a minor reduction of CCK-positive cells; no changes in SOM-positive cells were observed. The overall reduction of interneurons was verified by quantification of GAD67-immunoreactive cells (-24% in ErbB4-/- mice). The reduction of interneurons along the dorsoventral axis was more severe in intermediate and ventral portions than in the dorsal hippocampus, and regional reductions occurred in the CA1-3 regions and subiculum, whereas we found no significant changes in the dentate gyrus (DG). The expression by different populations of interneurons suggests that ErbB4 can modulate several microcircuits within the hippocampus and mediate the previously reported effects of NRG1 on network oscillations and synaptic plasticity. The selective reduction of GABAergic cells in ErbB4-/- mice is consistent with the role of NRG-ErbB4 signaling in the generation and migration of interneurons during development, and with neuronal and behavioral functional deficits in adult ErbB4 knockouts.
神经调节蛋白（NRGs）是表皮生长因子受体酪氨酸激酶的配体。NRG1-ErbB4 途径已被证明可以调节成年啮齿动物大脑中海马突触可塑性和网络振荡。为了确定介导这些效应的细胞，我们在这里确定了 ErbB4 在成年海马体中代表大多数抑制性神经元的四个功能不同的中间神经元类群中的表达模式。基于来自九只小鼠和 25000 个细胞的数据，我们表明 ErbB4 在胆囊收缩素（CCK，54%）、副甲状腺蛋白（PV，42%）或神经元一氧化氮合酶（nNOS，39%）阳性的细胞中以层特异性和区域特异性的方式表达，而表达生长抑素（SOM）的细胞很少对 ErbB4 有免疫反应性（1%）。接下来，我们比较了 ErbB4-/- 小鼠和野生型对照之间中间神经元的数量密度（细胞/mm(3)）和分布。基于来自 25 只小鼠和 56000 个细胞的数据，我们检测到 PV 阳性和 nNOS 阳性细胞的减少（分别减少 24%和 27%），但 CCK 阳性细胞的减少较少；未观察到 SOM 阳性细胞的变化。通过定量 GAD67 免疫反应性细胞（ErbB4-/- 小鼠减少 24%）证实了中间神经元的整体减少。沿背腹轴的中间神经元减少在中间和腹侧部分比在背侧海马更严重，并且在 CA1-3 区域和下托区发生区域性减少，而在齿状回（DG）中未发现明显变化。不同中间神经元群体的表达表明 ErbB4 可以调节海马内的几个微电路，并介导 NRG1 对网络振荡和突触可塑性的先前报道的影响。ErbB4-/- 小鼠中 GABA 能神经元的选择性减少与 NRG-ErbB4 信号在发育过程中中间神经元的产生和迁移中的作用以及成年 ErbB4 敲除小鼠中的神经元和行为功能缺陷一致。
