Functional and Phenotypic Regulation of GABAergic Development with Neurotrophic Factors

GABA能神经元在脑功能中起着重要作用，可以减弱兴奋性神经传递，产生振荡活动模式，调节发育可塑性和关键期。最近，我们发现EGF家族的神经营养因子与自闭症和精神分裂症等发育性脑部疾病有关。在本项目中，我们计划探索表皮生长因子样因子对GABA能神经元及其亚型(S)的生理活性、细胞信号转导和病理贡献。在皮质GABA能神经元的不同亚型中，小白蛋白阳性的GABA神经元携带ErbB4并与NeuRegin-1反应。该因子增加AMPA型谷氨酸受体的表达，更有效地产生GABA释放，并产生更强的突触后抑制。同类型的GABA能神经元也表达ErbB1并对EGF有反应，尽管反应的方向完全相反；EGF下调谷氨酸受体水平和谷氨酸脱羧酶的表达，在突触后神经元引起较轻微的抑制。相反，同样的因子，EGF，对苍白球GABA神经元施加了不同的作用；它提高了这些神经元的兴奋性，使这些神经元能够在靶区释放更多的GABA。因此，这些发现表明，大脑中的GABA能神经元具有与EGF样因子反应的动态可塑性，但表型反应的方向和幅度明显不同于GABA能神经元的不同亚型。

GABAergic neurons play crucial roles in the brain functions, attenuating excitatoryneurotransmission, generating oscillation activity patterns, and regulating developmentalplasticity and critical periods. Recently, we implicate neurotrophic factors of the EGFfamily in the brain diseases of developmental origin such as autism and schizophrenia. Inthe present project, we planed to explore the physiological activity, cellular signaling, and pathologic contribution of EGF-like factors’ actions on GABAergic neurons and theirsubtype(s). Among various subtypes of cortical GABAergic neurons, parvalbumin-positiveGABA neurons carried ErbB4 and reacted with neuregulin-1. This factor elevated theexpression of AMPA-type glutamate receptors, more efficiently derived GABA release, andproduced stronger postsynaptic inhibition. The same type of GABAergic neurons expressedErbB1 and responded to EGF as well, although the direction of the reaction was totallyopposite; EGF down-regulated the glutamate receptor levels and glutamate aciddecarboxylase expression, provoking more modest inhibition in postsynaptic neurons. Incontrast, the same factor, EGF, exerted a distinct action on pallidal GABA neurons; itelevated the excitability of these neurons and enabled those to release more amounts ofGABA in the target region. Therefore, these findings suggest that GABAergic neurons inthe brain harbor dynamic plasticity to react with EGF-like factors but the direction andmagnitude of the phenotypic responses differ significantly depending on individualsubtypes of GABAergic neurons.