Long-term exposure to dieldrin reduces γ-aminobutyric acid type A and N-methyl-D-aspartate receptor function in primary cultures of mouse cerebellar granule cells
Long-term exposure to dieldrin reduces γ-aminobutyric acid type A and N-methyl-D-aspartate receptor function in primary cultures of mouse cerebellar granule cells
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DOI：
10.1002/jnr.21433
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发表时间：
2007-12-01
影响因子：
4.2
通讯作者：
Sunol, Cristina
中科院分区：
文献类型：
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作者：
Babot, Zoila;Vilaro, M. Teresa;Sunol, Cristina
有机氯农药狄氏剂是一种持久性有机污染物，在生物体的脂肪组织中积累。在哺乳动物中，它拮抗GABA（A）受体，在急性接触后产生惊厥。虽然有报告称狄氏剂在人脑中蓄积，但对长期接触狄氏剂对神经系统的影响知之甚少。据报道，当神经元活动长期改变时，兴奋和抑制之间的平衡会受到稳态控制。我们假设，非细胞毒性浓度的狄氏剂可以减少GABA（A）受体功能长期降低的结果，海马能神经传递。通过GABA诱导的Cl-36吸收测量，原代小脑颗粒细胞培养物长期暴露于3 μ M狄氏剂，GABA（A）受体功能降低至对照组的55%。通过Western印迹法测定，该暴露导致NMDA诱导的[Ca 2 +]i增加和[H-3]MK-801结合显著降低（约35%），但未伴随NMDA受体亚基NR 1降低。与NMDA受体功能降低一致，狄氏剂处理的培养物对暴露于高钾诱导的兴奋性毒性刺激不敏感。总之，我们报告了狄氏剂诱导的GABA（A）受体功能的慢性降低减少了功能性NMDA受体的数量，这可能归因于突触缩放的机制。这些影响可能是低水平暴露于狄氏剂引起认知障碍的神经机制的基础。(C)2007 Wiley-Liss，Inc.
The organochlorine pesticide dieldrin is a persistent organic pollutant that accumulates in the fatty tissue of living organisms. In mammals, it antagonizes the GABA(A) receptor, producing convulsions after acute exposure. Although accumulation in human brain has been reported, little is known about the effects of longterm exposure to dieldrin in the nervous system. Homeostatic control of the balance between excitation and inhibition has been reported when neuronal activity is chronically altered. We hypothesized that noncytotoxic concentrations of dieldrin could decrease glutamatergic neurotransmission as a consequence of a prolonged reduction in GABA(A) receptor function. Longterm exposure of primary cerebellar granule cell cultures to 3 mu M dieldrin reduced the GABA(A) receptor function to 55% of control, as measured by the GABA-induced Cl-36- uptake. This exposure produced a significant reduction (similar to 35%) of the NMDA-induced increase in [Ca2+]i and of the [H-3]MK-801 binding, which was not accompanied by a reduction in the NMDA receptor subunit NR1, as determined by Western blot. Consistent with the decreased NMDA receptor function, dieldrin-treated cultures were insensitive to an excitotoxic stimulus induced by exposure to high potassium. In summary, we report that the chronic reduction of GABA(A) receptor function induced by dieldrin decreases the number of functional NMDA receptors, which may be attributable to a mechanism of synaptic scaling. These effects could underlie neural mechanisms involved in cognitive impairment produced by low-level exposure to dieldrin. (C) 2007 Wiley-Liss, Inc.