Namba Hisaaki, Nagano Tadasato, Jodo Eiichi, Eifuku Satoshi, Horie Masao, Takebayashi Hirohide, Iwakura Yuriko, Sotoyama Hidekazu, Takei Nobuyuki, Nawa Hiroyuki
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan.
Department of Health and Nutrition, University of Niigata Prefecture, Higashi-ku, Niigata, Japan.
J Neurochem. 2017 Sep;142(6):886-900. doi: 10.1111/jnc.14097. Epub 2017 Jul 11.
Phenotypic development of neocortical GABA neurons is highly plastic and promoted by various neurotrophic factors such as neuregulin-1. A subpopulation of GABA neurons expresses not only neuregulin receptor (ErbB4) but also epidermal growth factor (EGF) receptor (ErbB1) during development, but the neurobiological action of EGF on this cell population is less understood than that of neuregulin-1. Here, we examined the effects of exogenous EGF on immature GABA neurons both in culture and in vivo and also explored physiological consequences in adults. We prepared low density cultures from the neocortex of rat embryos and treated neocortical neurons with EGF. EGF decreased protein levels of glutamic acid decarboxylases (GAD65 and GAD67), and EGF influences on neuronal survival and glial proliferation were negligible or limited. The EGF treatment also diminished the frequency of miniature inhibitory postsynaptic currents (mIPSCs). In vivo administration of EGF to mouse pups reproduced the above GABAergic phenomena in neocortical culture. In EGF-injected postnatal mice, GAD- and parvalbumin-immunoreactivities were reduced in the frontal cortex. In addition, postnatal EGF treatment decreased mIPSC frequency in, and the density of, GABAergic terminals on pyramidal cells. Although these phenotypic influences on GABA neurons became less marked during development, it later resulted in the reduced β- and γ-powers of sound-evoked electroencephalogram in adults, which is regulated by parvalbumin-positive GABA neurons and implicated in the schizophrenia pathophysiology. These findings suggest that, in contrast to the ErbB4 ligand of neuregulin-1, the ErbB1 ligand of EGF exerts unique maturation-attenuating influences on developing cortical GABAergic neurons.
新皮质GABA神经元的表型发育具有高度可塑性，并受到多种神经营养因子（如神经调节蛋白-1）的促进。在发育过程中，GABA神经元的一个亚群不仅表达神经调节蛋白受体（ErbB4），还表达表皮生长因子（EGF）受体（ErbB1），但与神经调节蛋白-1相比，人们对EGF在该细胞群体上的神经生物学作用了解较少。在这里，我们研究了外源性EGF对培养物和体内未成熟GABA神经元的影响，并探讨了其对成年个体的生理影响。我们从大鼠胚胎的新皮质制备了低密度培养物，并用EGF处理新皮质神经元。EGF降低了谷氨酸脱羧酶（GAD65和GAD67）的蛋白质水平，并且EGF对神经元存活和神经胶质细胞增殖的影响可以忽略不计或有限。EGF处理还降低了微小抑制性突触后电流（mIPSCs）的频率。对幼鼠进行体内注射EGF可重现上述新皮质培养物中的GABA能现象。在注射EGF的出生后小鼠中，额叶皮质中GAD和小白蛋白免疫反应性降低。此外，出生后EGF处理降低了锥体细胞上GABA能终末的mIPSC频率和密度。尽管这些对GABA神经元的表型影响在发育过程中变得不那么明显，但后来导致成年个体中声音诱发脑电图的β和γ功率降低，这由小白蛋白阳性GABA神经元调节，并与精神分裂症的病理生理学有关。这些发现表明，与神经调节蛋白-1的ErbB4配体相反，EGF的ErbB1配体对发育中的皮质GABA能神经元具有独特的成熟减弱影响。
