Alterations in long-term seizure susceptibility and the complex of PSD-95 with NMDA receptor from animals previously exposed to perinatal hypoxia
Alterations in long-term seizure susceptibility and the complex of PSD-95 with NMDA receptor from animals previously exposed to perinatal hypoxia
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DOI：
10.1111/j.1528-1167.2006.00420.x
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发表时间：
2006-02-01
期刊：
影响因子：
5.6
通讯作者：
Yang, SN
中科院分区：
文献类型：
--
作者：
Chen, WF;Chang, H;Yang, SN
目的：围产期缺氧是新生儿脑损伤的一个重要原因，并具有潜在的破坏性和终身的后果，如在以后的生活中癫痫的风险增加。突触后密度（PSD）是一种细胞骨架特化，参与神经递质受体的锚定和调节突触后神经元对突触刺激的反应。突触后蛋白PSD-95与N-甲基-D-天冬氨酸受体（NMDAR）亚基结合，并因此激活NMDAR介导的事件的级联，例如丝氨酸-133处的环磷酸腺苷（cAMP）-响应元件结合蛋白磷酸化（pCREB（丝氨酸-133））。在这里，我们研究了围产期缺氧对PSD-95和NMDAR的蛋白质相互作用的影响，以及pCREB（Ser-133）的表达在一个年龄时，动物表现出增加的癫痫susceptibility.Methods：大鼠随机分配到对照组大鼠或大鼠暴露于出生后第10天（P10）短暂的全球缺氧。在P45，两组中的一些大鼠用戊四氮（PTZ）腹腔内处理以测试癫痫发作阈值，而另一些则研究神经元损失、pCREB分别采用免疫组化、免疫共沉淀和免疫印迹技术检测中脑、颞叶皮质和海马CA 1区的丝氨酸-133、PSD-95和NMDAR表达。与对照组相比，围产期缺氧大鼠癫痫发作的易感性增加。与癫痫发作易感性的长期变化相关，在中脑区域观察到选择性神经元丢失，而pCREB（Ser-133）表达在中脑、颞叶皮质和海马CA 1区减少。围产期缺氧导致中脑和海马CA 1区PSD-95表达减少，颞叶皮质除外。此外，PSD-95和NMDAR亚基（NR 1，NR 2A，和NR 2B）在海马CA 1之间的关联也显着改变围产期hypoxia.Conclusions：本研究表明，在几个蛋白复合物，是突触后装置的重要组成部分的减少与观察到的癫痫发作易感性在成年大鼠与前暴露于围产期缺氧。结果表明，PSD-95的表达，PSD-95结合的NMDAR亚基，和随后的NMDAR介导的CREB磷酸化，特别是在海马CA 1区，是围产期缺氧的长期后果，并可能，至少部分，有助于围产期缺氧诱导的癫痫发作阈值降低。
Purpose: Perinatal hypoxia is an important cause of brain injury in the newborn and has consequences that are potentially devastating and life-long, such as an increased risk of epilepsy in later life. The postsynaptic density (PSD) is a cytoskeletal specialization involved in the anchoring of neurotransmitter receptors and in regulating the response of postsynaptic neurons to synaptic stimulation. The postsynaptic protein PSD-95 binds to the N-methyl-D-aspartate receptor (NMDAR) subunit, and hence activates cascades of NMDAR-mediated events, such as cyclic adenosine monophosphate (cAMP)-responsive element binding protein phosphorylation at serine-133 (pCREB(Serine-133)). Here we studied the effect of perinatal hypoxia on protein interactions involving PSD-95 and the NMDAR, as well as pCREB(Ser-133) expression at an age when the animals show increased seizure susceptibility.Methods: Rats were assigned randomly to the control rats or the rats exposed to transient global hypoxia at postnatal day 10 (P10). At P45, some rats from both groups were treated with pentylenetetrazol (PTZ) intraperitoneally to test the seizure threshold, and others were studied for neuronal loss, pCREB(Serine-133), PSD-95, and NMDAR expressions in the midbrain, temporal cortex, and hippocampal CA1 subfield by using immunohistochemistry, co-immunoprecipitation, and immunoblotting techniques, respectively.Results: The rats with prior exposure to perinatal hypoxia exhibited increased seizure susceptibility to PTZ, compared with the control rats. Associated with this long-term change in seizure susceptibility, selective neuronal loss was observed in the midbrain region while pCREB(Ser-133) expression was reduced in the midbrain, temporal cortex, and hippocampal CA1 subfield. Perinatal hypoxia led to a decrease in PSD-95 expression in the both midbrain and hippocampal CA1 subfield, with the exception of temporal cortex. Furthermore, the association between PSD-95 and NMDAR subunits (NR1, NR2A, and NR2B) in the hippocampal CA1 was also markedly altered by perinatal hypoxia.Conclusions: This study demonstrates that the decrease in several protein complexes that are essential components of the postsynaptic apparatus is associated with the observed increase in seizure susceptibility in adult rats with prior exposure to perinatal hypoxia. The results indicate that reductions in PSD-95 expression, PSD-95 binding of NMDAR subunits, and subsequent NMDAR-mediated CREB phosphorylation, particularly in hippocampal CA1, are long-term consequences of perinatal hypoxia and may, at least in part, contribute to perinatal hypoxia-induced reduction in seizure threshold.