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Changes in synaptic AMPA receptor concentration and composition in chronic temporal lobe epilepsy
Molecular and Cellular Neuroscience ( IF 3.5 ) Pub Date : 2018-07-29 , DOI: 10.1016/j.mcn.2018.07.004
Daniel L. Egbenya , Suleman Hussain , Yi-Chen Lai , Jun Xia , Anne E. Anderson , Svend Davanger

Excitotoxicity caused by excessive stimulation of glutamate receptors, resulting in pathologically increased Ca2+-concentrations, is a decisive factor in neurodegenerative diseases. We investigated long-term changes in synaptic contents of AMPA receptor subunits that play important roles in calcium regulation in chronic epilepsy. Such plastic changes may be either adaptive or detrimental. We used a kainic acid (KA)-based rat model of chronic temporal lobe epilepsy (TLE). Using hippocampal synaptosomes, we found significant reductions in the concentration of the AMPA receptor subunits GluA1 and GluA2, and the NMDA receptor subunit NR2B. The relative size of GluA1 and GluA2 reductions were almost identical, at 28% and 27%, respectively. In order to determine whether the synaptic reduction of the AMPA receptor subunits actually reflected the pool of receptors present along the postsynaptic density (PSD), as opposed to cytoplasmic or extrasynaptic pools, we performed postembedding immunogold electron microscopy (EM) of GluA1 and GluA2 in Schaffer collateral synapses in the hippocampal CA1 area. We found significant reductions, at 32% and 52% of GluA1 and GluA2 subunits, respectively, along the PSD, indicating that these synapses undergo lasting changes in glutamatergic neurotransmission during chronic TLE. When compared to the overall concentration and composition of AMPA receptors expressed in the brain, there was a relative increase in GluA2-lacking AMPA receptor subunits following chronic epilepsy. These changes in synaptic AMPA receptor subunits may possibly contribute to further aggravate the excitotoxic vulnerability of the neurons as well as have significant implications for hippocampal cognitive functions.



中文翻译:

慢性颞叶癫痫中突触AMPA受体浓度和组成的变化

谷氨酸受体过度刺激引起的兴奋性毒性,导致Ca 2+在病理上增加-浓度,是神经退行性疾病的决定性因素。我们调查了AMPA受体亚基的突触内容的长期变化,这些变化在慢性癫痫的钙调节中起重要作用。这种塑性变化可能是适应性的,也可能是有害的。我们使用了基于凯南酸(KA)的慢性颞叶癫痫(TLE)大鼠模型。使用海马突触小体,我们发现AMPA受体亚基GluA1和GluA2以及NMDA受体亚基NR2B的浓度显着降低。GluA1和GluA2减少量的相对大小几乎相同,分别为28%和27%。为了确定AMPA受体亚基的突触减少是否实际反映了沿突触后密度(PSD)的受体池,而不是胞浆或突触外池,我们在海马CA1区的Schaffer侧突触中进行了GluA1和GluA2的包埋后免疫金电子显微镜(EM)。我们发现,沿着PSD,分别显着减少了GluA1和GluA2亚基的32%和52%,这表明这些突触在慢性TLE期间发生了谷氨酸能神经传递的持久变化。与大脑中表达的AMPA受体的总体浓度和组成相比,慢性癫痫后缺少GluA2的AMPA受体亚单位相对增加。突触AMPA受体亚基的这些变化可能有助于进一步加重神经元的兴奋毒性,并对海马认知功能产生重大影响。

更新日期:2018-07-29
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