Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in the P/Q-type calcium channel
Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in the P/Q-type calcium channel
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DOI：
10.1073/pnas.1009500107
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发表时间：
2010-10-26
影响因子：
11.1
通讯作者：
Snutch, Terrance P.
中科院分区：
文献类型：
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作者：
Adams, Paul J.;Rungta, Ravi L.;Snutch, Terrance P.
神经回路的动力学、计算能力和强度对于中枢神经系统中的信息编码和处理至关重要，并且依赖于短形式和长形式的突触可塑性。在模型系统中，突触前末梢中的残留钙（Ca2+）可以通过神经元Ca2+传感器蛋白起作用，引起P/Q型通道的Ca2+依赖性易化（CDF）并诱导短期突触易化。然而，据我们所知，这是否是完整中央突触可塑性的一般机制以及与人类疾病相关的突变是否影响这一过程尚未得到描述。在本报告中，我们发现，在外源性和天然制剂中，家族性偏瘫性偏头痛 1 型 (FHM-1) 潜在的功能获得性错义突变会阻塞 P/Q 型 Ca2+ 通道的 CDF。在 FHM-1 突变小鼠中，P/Q 型通道 CDF 的改变与小脑平行纤维至浦肯野细胞突触的短期突触促进减少相关。双光子成像表明 FHM-1 小鼠平行纤维末端的 P/Q 型通道处于基底促进状态。总体而言，结果提供证据表明 FHM-1 突变直接影响 P/Q 型通道 CDF 和突触可塑性，并且它们共同可能促成 FHM-1 的病理生理学。研究结果还表明，P/Q 型通道 CDF 是哺乳动物中枢神经系统快速突触正常突触可塑性所需的重要机制。
The dynamics, computational power, and strength of neural circuits are essential for encoding and processing information in the CNS and rely on short and long forms of synaptic plasticity. In a model system, residual calcium (Ca2+) in presynaptic terminals can act through neuronal Ca2+ sensor proteins to cause Ca2+-dependent facilitation (CDF) of P/Q-type channels and induce short-term synaptic facilitation. However, whether this is a general mechanism of plasticity at intact central synapses and whether mutations associated with human disease affect this process have not been described to our knowledge. In this report, we find that, in both exogenous and native preparations, gain-of-function missense mutations underlying Familial Hemiplegic Migraine type 1 (FHM-1) occlude CDF of P/Q-type Ca2+ channels. In FHM-1 mutant mice, the alteration of P/Q-type channel CDF correlates with reduced short-term synaptic facilitation at cerebellar parallel fiber-to-Purkinje cell synapses. Two-photon imaging suggests that P/Q-type channels at parallel fiber terminals in FHM-1 mice are in a basally facilitated state. Overall, the results provide evidence that FHM-1 mutations directly affect both P/Q-type channel CDF and synaptic plasticity and that together likely contribute toward the pathophysiology underlying FHM-1. The findings also suggest that P/Q-type channel CDF is an important mechanism required for normal synaptic plasticity at a fast synapse in the mammalian CNS.