Furukawa Minami, Tsukahara Takao, Tomita Kazuo, Iwai Haruki, Sonomura Takahiro, Miyawaki Shouichi, Sato Tomoaki
Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan; Department of Orthodontics and Dentofacial Orthopedics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
Biochem Biophys Res Commun. 2017 Nov 25;493(3):1243-1249. doi: 10.1016/j.bbrc.2017.09.143. Epub 2017 Sep 28.
The excitatory-to-inhibitory functional switch of γ-aminobutyric acid (GABA; GABA switch), which normally occurs in the first to the second postnatal week in the hippocampus, is necessary for the development of appropriate central nervous system function. A deficit in GABAergic inhibitory function could cause excitatory/inhibitory (E/I) neuron imbalance that is found in many neurodegenerative disorders. In the present study, we examined whether neonatal stress can affect the timing of the GABA functional switch and cause disorders during adolescence. Neonatal stress was induced in C57BL/6J male mouse pups by maternal separation (MS) on postnatal days (PND) 1-21. Histological quantification of K-Cl co-transporter (KCC2) and Ca imaging were performed to examine the timing of the GABA switch during the MS period. To evaluate the influence of neonatal MS on adolescent hippocampal function, we quantified KCC2 expression and evaluated hippocampal-related behavioral tasks at PND35-38. We showed that MS delayed the timing of the GABA switch in the hippocampus and inhibited the increase in membrane KCC2 expression, with KCC2 expression inhibition persisting until adolescence. Behavioral tests showed impaired cognition, declined attention, hyperlocomotion, and aggressive character in maternally separated mice. Taken together, our results show that neonatal stress delayed the timing of the GABA switch, which could change the E/I balance and cause neurodegenerative disorders in later life.
γ-氨基丁酸（GABA）的兴奋-抑制功能转换（GABA转换）通常发生在海马体出生后第一周到第二周，这对中枢神经系统功能的正常发育至关重要。GABA能抑制功能的缺陷可能导致兴奋性/抑制性（E/I）神经元失衡，这在许多神经退行性疾病中都有发现。在本研究中，我们研究了新生儿应激是否会影响GABA功能转换的时间，并在青春期引发疾病。通过在出生后第1 - 21天对C57BL/6J雄性幼鼠进行母婴分离（MS）来诱导新生儿应激。进行K-Cl共转运体（KCC2）的组织学定量分析和钙成像，以检查MS期间GABA转换的时间。为了评估新生儿MS对青春期海马体功能的影响，我们在出生后第35 - 38天对KCC2表达进行了定量分析，并评估了与海马体相关的行为任务。我们发现，MS延迟了海马体中GABA转换的时间，并抑制了膜KCC2表达的增加，KCC2表达抑制一直持续到青春期。行为测试显示，母婴分离小鼠存在认知障碍、注意力下降、活动亢进和攻击性增强的问题。综上所述，我们的结果表明，新生儿应激延迟了GABA转换的时间，这可能会改变E/I平衡，并在以后的生活中引发神经退行性疾病。
