Murase Sachiko
Laboratory of Molecular Biology, National Institute of Neurological Disorder and Stroke, National Institutes of Health, 35 Lincoln Dr., Bethesda, MD, 20892, USA,
Mol Neurobiol. 2014 Feb;49(1):316-25. doi: 10.1007/s12035-013-8521-8. Epub 2013 Aug 13.
The nervous system develops through a program that produces neurons in excess and then eliminates approximately half during a period of naturally occurring death. Neuronal activity has been shown to promote the survival of neurons during this period by stimulating the production and release of neurotrophins. In the peripheral nervous system (PNS), neurons depends on neurotrophins that activate survival pathways, which explains how the size of target cells influences number of neurons that innervate them (neurotrophin hypothesis). However, in the central nervous system (CNS), the role of neurotrophins has not been clear. Contrary to the neurotrophin hypothesis, a recent study shows that, in neonatal hippocampus, neurotrophins cannot promote survival without spontaneous network activity: Neurotrophins recruit neurons into spontaneously active networks, and this activity determines which neurons survive. By placing neurotrophin upstream of activity in the survival signaling pathway, these new results change our understanding of how neurotrophins promote survival. Spontaneous, synchronized network activity begins to spread through both principle neurons and interneurons in the hippocampus as they enter the death period. At this stage, neurotransmission mediated by γ-aminobutyric acid (GABA) is excitatory and drives the spontaneous activity. An important recent observation is that neurotrophins preferentially recruit GABAergic neurons into spontaneously active networks; thus, neurotrophins select for survival only those neurons joined to active networks with strong GABAergic inputs, which would later become inhibitory. A proper excitatory/inhibitory (E/I) balance is critical for normal adult brain function. This balance may be especially important in the hippocampus where impairments in E/I balance are associated with pathologies including epilepsy. Here, I discuss the molecular mechanisms for survival in neonatal neurons, how these mechanisms change during development, and how they may be linked to degenerative diseases.
神经系统通过一个程序发育，该程序会产生过量的神经元，然后在自然发生死亡的时期内消除大约一半。研究表明，神经元活动可通过刺激神经营养因子的产生和释放来促进这一时期神经元的存活。在周围神经系统（PNS）中，神经元依赖于激活存活途径的神经营养因子，这解释了靶细胞的大小如何影响支配它们的神经元数量（神经营养因子假说）。然而，在中枢神经系统（CNS）中，神经营养因子的作用尚不清楚。与神经营养因子假说相反，最近的一项研究表明，在新生海马体中，神经营养因子在没有自发网络活动的情况下无法促进存活：神经营养因子将神经元招募到自发活动的网络中，而这种活动决定了哪些神经元能够存活。通过将神经营养因子置于存活信号通路中活动的上游，这些新结果改变了我们对神经营养因子如何促进存活的理解。当海马体中的主要神经元和中间神经元进入死亡期时，自发的同步网络活动开始在它们之间传播。在这个阶段，由γ-氨基丁酸（GABA）介导的神经传递是兴奋性的，并驱动自发活动。最近一项重要的观察结果是，神经营养因子优先将GABA能神经元招募到自发活动的网络中；因此，神经营养因子只选择那些与具有强大GABA能输入的活跃网络相连的神经元存活，这些神经元随后将变成抑制性神经元。适当的兴奋/抑制（E/I）平衡对于正常的成人大脑功能至关重要。这种平衡在海马体中可能尤为重要，因为E/I平衡受损与包括癫痫在内的多种病理状况有关。在此，我将讨论新生神经元存活的分子机制、这些机制在发育过程中如何变化，以及它们如何与退行性疾病相关联。
