Enhanced Excitatory Transmission at Cortical Synapses as the Basis for Facilitated Spreading Depression in Cav2.1 Knockin Migraine Mice
Enhanced Excitatory Transmission at Cortical Synapses as the Basis for Facilitated Spreading Depression in Cav2.1 Knockin Migraine Mice
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DOI：
10.1016/j.neuron.2009.01.027
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发表时间：
2009-03-12
期刊：
影响因子：
16.2
通讯作者：
Pietrobon, Daniela
中科院分区：
文献类型：
--
作者：
Tottene, Angelita;Conti, Rossella;Pietrobon, Daniela
偏头痛是一种常见的致残性大脑疾病。有先兆的偏头痛的一种亚型(家族性偏瘫偏头痛1型：FHM1)是由Ca(V)2.1(P/Q型)钙通道突变引起的。携带FHM1突变的Knockin小鼠表现出神经元P/Q型电流增加，并促进皮质扩散性抑制(CSD)的诱导和传播，这一现象是偏头痛先兆的基础，并可能激活偏头痛机制。我们在FHM1小鼠的神经元微培养和脑片中研究了皮质神经传递。我们发现，兴奋性神经传递功能的增强是由于动作电位引起的钙内流增加，锥体细胞突触释放谷氨酸的可能性增加，而在快速放电的神经元间突触，兴奋性神经传递的抑制性神经传递没有改变。使用CSD的体外模型，我们显示了促进谷氨酸释放和CSD易化之间的因果联系。FHM1突变的突触特异性效应表明，兴奋-抑制平衡的破坏和神经元的过度活动是偏头痛发作性CSD点火易感性的基础。
Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in Ca(v)2.1 (P/Q-type) Ca2+ channels. Knockin mice carrying a FHM1 mutation show increased neuronal P/Q-type current and facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. We studied cortical neurotransmission in neuronal microcultures and brain slices of FHM1 mice. We show gain of function of excitatory neurotransmission due to increased action-potential-evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses. Using an in vitro model of CSD, we show a causative link between enhanced glutamate release and CSD facilitation. The synapse-specific effect of FHM1 mutations points to disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for episodic vulnerability to CSD ignition in migraine.