Ablation of NMDA Receptors Enhances the Excitability of Hippocampal CA3 Neurons
Ablation of NMDA Receptors Enhances the Excitability of Hippocampal CA3 Neurons
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DOI：
10.1371/journal.pone.0003993
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发表时间：
2009-01-14
期刊：
影响因子：
3.7
通讯作者：
Mishina, Masayoshi
中科院分区：
文献类型：
--
作者：
Fukushima, Fumiaki;Nakao, Kazuhito;Mishina, Masayoshi
海马CA3循环网络的同步放电被认为是网络振荡、记忆形成和癫痫发作的基础。在海马CA3网络中，NMDA受体在复发突触中丰富，而在苔藓纤维突触中较少。我们在出生后第14天产生了海马CA3锥体神经元中NMDA受体被废除的突变小鼠。对照和突变小鼠海马CA3区的组织学和细胞学组织没有区别。我们发现CA3锥体神经元中选择性缺乏NMDA受体的突变小鼠更容易发生盐酸盐诱导的癫痫发作。与此一致的是，突变小鼠表现出与多单位活动（MUA）相关的特征性大脑电图峰，表明CA3神经元的同步放电增强。海马CA3区的快速兴奋性和抑制性突触传递的电生理平衡在对照和突变锥体神经元之间具有可比性，而在突变神经元中，NMDA受体-慢速AHP耦合减弱。在成人大脑中，Cre重组酶的病毒表达载体诱导海马CA3区NMDA受体消融也诱导了类似的大脑电图峰。此外，药物阻断CA3 NMDA受体增加了对盐酸盐诱导的癫痫发作的易感性。这些结果提出了一种有趣的可能性，即海马CA3 NMDA受体可能通过限制CA3神经元的同步放电来抑制体内整个循环网络的兴奋性。
Synchronized discharges in the hippocampal CA3 recurrent network are supposed to underlie network oscillations, memory formation and seizure generation. In the hippocampal CA3 network, NMDA receptors are abundant at the recurrent synapses but scarce at the mossy fiber synapses. We generated mutant mice in which NMDA receptors were abolished in hippocampal CA3 pyramidal neurons by postnatal day 14. The histological and cytological organizations of the hippocampal CA3 region were indistinguishable between control and mutant mice. We found that mutant mice lacking NMDA receptors selectively in CA3 pyramidal neurons became more susceptible to kainate-induced seizures. Consistently, mutant mice showed characteristic large EEG spikes associated with multiple unit activities (MUA), suggesting enhanced synchronous firing of CA3 neurons. The electrophysiological balance between fast excitatory and inhibitory synaptic transmission was comparable between control and mutant pyramidal neurons in the hippocampal CA3 region, while the NMDA receptor-slow AHP coupling was diminished in the mutant neurons. In the adult brain, inducible ablation of NMDA receptors in the hippocampal CA3 region by the viral expression vector for Cre recombinase also induced similar large EEG spikes. Furthermore, pharmacological blockade of CA3 NMDA receptors enhanced the susceptibility to kainate-induced seizures. These results raise an intriguing possibility that hippocampal CA3 NMDA receptors may suppress the excitability of the recurrent network as a whole in vivo by restricting synchronous firing of CA3 neurons.