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Hypoxia regulates the level of glutamic acid decarboxylase enzymes and interrupts inhibitory synapse stability in primary cultured neurons
NeuroToxicology ( IF 3.4 ) Pub Date : 2017-10-28 , DOI: 10.1016/j.neuro.2017.10.006
Seojin Hwang , Sangwoo Ham , Seong-Eun Lee , Yunjong Lee , Gum Hwa Lee

Gamma-aminobutyric acid (GABA) is the main neurotransmitter of inhibitory synaptic transmission, which is critical for oscillatory activity and synchronization of neurons in neural networks. GABA is synthesized by glutamic acid decarboxylase (GAD) enzymes in the inhibitory neuron and, thus, the deregulation of GAD enzymes and subsequent change of GABAergic activity are involved in various neurological and neuropsychiatric diseases. Under hypoxic conditions, neurons undergo neuropathological alterations which can be subtle or severe. Many studies have focused on the alteration of excitatory neurons by hypoxic injury, while inhibitory neuronal changes have not been well determined. Here, we demonstrated that hypoxic conditions decrease the expression of inhibitory neuron-related proteins, including GAD enzymes, through transcript downregulation and proteasomal degradation. Hif-1α induction and glutamate release under hypoxic conditions were implicated in the mechanism of GAD enzyme level reduction. Surprisingly, these conditions altered the density and size of inhibitory synapses, which was irreversible by reoxygenation, but was mediated by glutamate activity. Our findings suggest that potential implication of the compositional and structural alterations of inhibitory neuron in the pathogenesis of various hypoxic injuries.



中文翻译:

缺氧调节谷氨酸脱羧酶的水平,并中断原代培养神经元的抑制性突触稳定性。

γ-氨基丁酸(GABA)是抑制性突触传递的主要神经递质,对神经网络中神经元的振荡活动和同步至关重要。GABA是由抑制性神经元中的谷氨酸脱羧酶(GAD)酶合成的,因此,GAD酶的失调和随后的GABA能活性变化涉及多种神经系统疾病和神经精神疾病。在缺氧条件下,神经元会发生细微或严重的神经病理改变。许多研究集中于缺氧性损伤引起的兴奋性神经元的改变,而抑制性神经元的变化尚未得到很好的确定。在这里,我们证明了低氧条件会降低抑制性神经元相关蛋白(包括GAD酶)的表达,通过转录下调和蛋白酶体降解。低氧条件下Hif-1α的诱导和谷氨酸的释放与GAD酶水平降低的机制有关。令人惊讶的是,这些条件改变了抑制性突触的密度和大小,这种抑制性突触是通过复氧作用不可逆的,但是是由谷氨酸的活性介导的。我们的发现表明,抑制性神经元的组成和结构改变在各种低氧损伤的发病机理中具有潜在的意义。

更新日期:2017-10-28
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