Repeated maternal separation causes transient reduction in BDNF expression in the medial prefrontal cortex during early brain development, affecting inhibitory neuron development
Repeated maternal separation causes transient reduction in BDNF expression in the medial prefrontal cortex during early brain development, affecting inhibitory neuron development
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DOI：
10.1016/j.heliyon.2020.e04781
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发表时间：
2020-08-01
期刊：
影响因子：
4
通讯作者：
Miki，Takanori
中科院分区：
文献类型：
--
作者：
Tenkumo，Chiaki;Ohta，Ken-ichi;Miki，Takanori
人们普遍认为，母亲分离（MS）会引起儿童的压力，并破坏早期大脑发育期间的神经回路形成。尽管这种破坏在生命早期短暂发生，但其影响在成熟后持续存在，并可能导致各种神经发育障碍。我们最近的研究表明，重复MS减少内侧前额叶皮层（mPFC）的抑制性神经元和突触的数量，并导致成熟后mPFC相关的社会缺陷。然而，MS如何在早期大脑发育过程中阻碍mPFC发育仍然知之甚少。在这里，我们专注于脑源性神经营养因子（BDNF）参与抑制性神经元的发展，并研究了时间依赖性BDNF的表达在断奶前暴露于MS的雄性大鼠的mPFC。我们的研究结果表明，MS衰减BDNF的表达只有在出生后的第一周结束。同样，MS组中活性调节的细胞因子相关蛋白（Arc）的mRNA表达也随着BDNF表达的减少而沿着下降，Arc是一种其表达部分受BDNF调节的即刻早期基因。相反，原肌球蛋白相关激酶B（Trk B），这是一种BDNF受体的mRNA表达几乎没有改变，而其蛋白质表达下降，在MS组仅在断奶期间。此外，MS降低谷氨酸脱羧酶（GAD）65，GABA合成酶的mRNA水平，只有在断奶期间。我们的研究结果表明，重复MS暂时减弱BDNF信号在大脑发育早期的mPFC。BDNF在抑制性神经元的发育中起着至关重要的作用;因此，BDNF信号的瞬时衰减可能导致mPFC中GABA能神经元发育的延迟。
It is widely accepted that maternal separation (MS) induces stress in children and disrupts neural circuit formation during early brain development. Even though such disruption occurs transiently early in life, its influence persists after maturation, and could lead to various neurodevelopmental disorders. Our recent study revealed that repeated MS reduces the number of inhibitory neurons and synapses in the medial prefrontal cortex (mPFC) and causes mPFC-related social deficits after maturation. However, how MS impedes mPFC development during early brain development remains poorly understood. Here, we focused on brain-derived neurotrophic factor (BDNF) involved in the development of inhibitory neurons, and examined time-dependent BDNF expression in the mPFC during the pre-weaning period in male rats exposed to MS. Our results show that MS attenuates BDNF expression only around the end of the first postnatal week. Likewise, mRNA expression of activity-regulated cytoskeleton-associated protein (Arc), an immediate-early gene whose expression is partly regulated by BDNF, also decreased in the MS group along with the reduction in BDNF expression. On the contrary, mRNA expression of tropomyosin-related kinase B (TrkB), which is a BDNF receptor, was scarcely altered, while its protein expression decreased in the MS group only during the weaning period. In addition, MS reduced mRNA levels of glutamic acid decarboxylase (GAD) 65, a GABA synthesizing enzyme, only during the weaning period. Our results suggest that repeated MS temporarily attenuates BDNF signaling in the mPFC during early brain development. BDNF plays a crucial role in the development of inhibitory neurons; therefore, transient attenuation of BDNF signaling may cause delays in GABAergic neuron development in the mPFC.