Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK.
Institute for Biomedical & Biomolecular Sciences, School of Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
J Neuroendocrinol. 2018 Feb;30(2). doi: 10.1111/jne.12537.
GABA plays a key role in both embryonic and neonatal brain development. For example, during early neonatal nervous system maturation, synaptic transmission, mediated by GABA receptors (GABA Rs), undergoes a temporally specific form of synaptic plasticity to accommodate the changing requirements of maturing neural networks. Specifically, the duration of miniature inhibitory postsynaptic currents (mIPSCs), resulting from vesicular GABA activating synaptic GABA Rs, is reduced, permitting neurones to appropriately influence the window for postsynaptic excitation. Conventionally, programmed expression changes to the subtype of synaptic GABA R are primarily implicated in this plasticity. However, it is now evident that, in developing thalamic and cortical principal- and inter-neurones, an endogenous neurosteroid tone (eg, allopregnanolone) enhances synaptic GABA R function. Furthermore, a cessation of steroidogenesis, as a result of a lack of substrate, or a co-factor, appears to be primarily responsible for early neonatal changes to GABAergic synaptic transmission, followed by further refinement, which results from subsequent alterations of the GABA R subtype. The timing of this cessation of neurosteroid influence is neurone-specific, occurring by postnatal day (P)10 in the thalamus but approximately 1 week later in the cortex. Neurosteroid levels are not static and change dynamically in a variety of physiological and pathophysiological scenarios. Given that GABA plays an important role in brain development, abnormal perturbations of neonatal GABA R-active neurosteroids may have not only a considerable immediate, but also a longer-term impact upon neural network activity. Here, we review recent evidence indicating that changes in neurosteroidogenesis substantially influence neonatal GABAergic synaptic transmission. We discuss the physiological relevance of these findings and how the interference of neurosteroid-GABA R interaction early in life may contribute to psychiatric conditions later in life.
GABA 在胚胎和新生儿大脑发育中都起着关键作用。例如，在早期新生儿神经系统成熟过程中，由 GABA 受体 (GABA Rs) 介导的突触传递经历了一种具有时间特异性的突触可塑性，以适应不断变化的成熟神经网络的需求。具体来说，囊泡 GABA 激活突触 GABA Rs 产生的微小抑制性突触后电流 (mIPSCs) 的持续时间缩短，使神经元能够适当影响突触后兴奋的窗口。传统上，突触 GABA R 亚类的程序性表达变化主要与这种可塑性有关。然而，现在很明显，在发育中的丘脑和皮质主神经元和中间神经元中，内源性神经甾体（例如，别孕烯醇酮）增强了突触 GABA R 的功能。此外，由于缺乏底物或辅助因子，类固醇生成的停止似乎是导致早期新生儿 GABA 能突触传递变化的主要原因，随后进一步细化，这是由于 GABA R 亚类随后的改变。这种神经甾体影响的停止时间是神经元特异性的，在丘脑中发生在出生后第 10 天（P10），但在皮质中大约晚 1 周。神经甾体水平不是静态的，而是在各种生理和病理生理情况下动态变化。鉴于 GABA 在大脑发育中起着重要作用，新生儿 GABA R 活性神经甾体的异常干扰不仅会对神经网络活动产生直接的影响，还会产生长期的影响。在这里，我们回顾了最近的证据，表明神经甾体生成的变化会显著影响新生儿 GABA 能突触传递。我们讨论了这些发现的生理相关性，以及生命早期神经甾体-GABA R 相互作用的干扰如何可能导致以后的精神疾病。
