Pan Y-Z, Rutecki P A
Department of Neurology, University of Wisconsin, Madison, WI 53705, United States.
Department of Neurology, University of Wisconsin, Madison, WI 53705, United States; William Middleton VA Memorial Hospital, Department of Neurology, 2500 Overlook Tr., Madison, WI 53705, United States.
Neuroscience. 2014 Sep 5;275:22-32. doi: 10.1016/j.neuroscience.2014.05.062. Epub 2014 Jun 11.
Prolonged activation of group I metabotropic glutamate receptors (mGluRs) using the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) produces long-lasting changes in the CA3 region of the hippocampal slice. Changes in CA3 pyramidal neuron excitability that follow DHPG exposure result in abnormal network activity manifest by epileptiform activity that consists of interictal and longer lasting ictal epileptiform discharges. In this study we evaluated changes in synaptic activity of CA3 neurons in rat hippocampal slices that occurred after exposure to DHPG. Whole-cell voltage-clamp recordings were made from visually identified CA3 neurons in control artificial cerebrospinal fluid at times greater than 1h after DHPG exposure. Compared to control slices, neurons from slices exposed to DHPG showed enhanced amplitude and frequency of spontaneously occurring excitatory postsynaptic currents (EPSCs) without a concurrent change in inhibitory postsynaptic current (IPSC) amplitude or frequency. Miniature EPSCs were not affected by DHPG exposure but mIPSCs occurred less frequently and were of reduced amplitude. IPSCs recorded in the presence of ionotropic glutamate receptor blockade occurred less frequently in neurons that had been exposed to DHPG. Monosynaptic-evoked IPSPs were also reduced in amplitude in neurons that had been exposed to DHPG. Taken together, these findings demonstrated an enhanced network excitability of the CA3 region and failure of compensatory synaptic inhibition. We propose that prolonged activation of group I mGluR that may occur under conditions of pathological glutamate release results in long-lasting changes in CA3 synaptic network activity and epileptiform activity driven by excessive synaptic excitation.
使用激动剂（S）-3,5-二羟基苯甘氨酸（DHPG）对I型代谢型谷氨酸受体（mGluRs）进行长时间激活，会在海马脑片的CA3区域产生持久变化。暴露于DHPG后CA3锥体神经元兴奋性的改变会导致异常的网络活动，表现为癫痫样活动，包括发作间期和持续时间更长的发作期癫痫样放电。在本研究中，我们评估了大鼠海马脑片暴露于DHPG后CA3神经元突触活动的变化。在DHPG暴露1小时以上的时间点，从对照人工脑脊液中视觉识别的CA3神经元进行全细胞电压钳记录。与对照脑片相比，暴露于DHPG的脑片中的神经元自发兴奋性突触后电流（EPSCs）的幅度和频率增强，而抑制性突触后电流（IPSC）的幅度或频率没有同时变化。微小EPSCs不受DHPG暴露的影响，但微小抑制性突触后电流（mIPSCs）出现的频率较低且幅度减小。在离子型谷氨酸受体阻断存在的情况下记录的IPSCs在暴露于DHPG的神经元中出现的频率较低。单突触诱发的抑制性突触后电位（IPSPs）在暴露于DHPG的神经元中幅度也降低。综上所述，这些发现表明CA3区域的网络兴奋性增强且代偿性突触抑制失败。我们提出，在病理性谷氨酸释放的情况下可能发生的I型mGluR的长时间激活，会导致CA3突触网络活动和由过度突触兴奋驱动的癫痫样活动的持久变化。
