Impaired Feedforward Inhibition of the Thalamocortical Projection in Epileptic Ca2+ Channel Mutant Mice, tottering
Impaired Feedforward Inhibition of the Thalamocortical Projection in Epileptic Ca2+ Channel Mutant Mice, tottering
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DOI：
10.1523/jneurosci.5422-05.2006
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发表时间：
2006-03
期刊：
影响因子：
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通讯作者：
S. Sasaki;K. Huda;Tsuyoshi Inoue;M. Miyata;K. Imoto
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作者：
S. Sasaki;K. Huda;Tsuyoshi Inoue;M. Miyata;K. Imoto
摇摇欲坠 (tg) 小鼠的 CaV2.1（P/Q 型）电压依赖性 Ca2+ 通道 α12.1 亚基基因发生突变。 tg 小鼠不仅表现出小脑性共济失调，而且还表现出失神性癫痫，这种现象在约 3 周龄时开始并持续终生。脑电图和抗癫痫药物敏感性的相似性表明 tg 小鼠是人类失神性癫痫的良好模型。尽管丘脑皮质网络中的兴奋性和抑制性活性之间的不平衡被认为是失神性癫痫的发病机制之一，但突变对丘脑皮质突触反应的影响仍然未知。在这里，我们使用脑切片制剂显示了 tg 小鼠抑制性突触反应的不平衡损伤。体感丘脑皮质投射不仅在第四层神经元上形成单突触谷氨酸能连接，而且还形成介导前馈抑制的非突触 GABA 能连接。在 tg 小鼠中，与发育后期（出生后 21-30 天）的 EPSC 振幅相比，体感皮层第四层锥体细胞响应丘脑刺激记录的 IPSC 振幅不成比例地降低。通过局部刺激第四层锥体神经元也获得了类似的结果。然而，在癫痫发作前（出生后第 14-16 天），癫痫 tg 小鼠的 V 层锥体神经元或年轻 tg 小鼠的 IV 层锥体神经元中未观察到 IPSC 减少。这些结果表明，tg小鼠中从丘脑到体感皮层第四层神经元的前馈抑制严重受损，并且抑制性突触传递的受损与失神性癫痫的发作相关。
The tottering (tg) mice have a mutation in the CaV2.1 (P/Q-type) voltage-dependent Ca2+ channel α12.1 subunit gene. tg mice show not only cerebellar ataxia but also absence epilepsy, which begins at ∼3 weeks of age and persists throughout life. Similarities in EEG and sensitivity to antiepileptic drugs suggest that tg mice are a good model for human absence epilepsy. Although imbalance between excitatory and inhibitory activity in the thalamocortical network is thought to contribute to the pathogenesis of absence epilepsy, the effect of the mutation on thalamocortical synaptic responses remains unknown. Here we showed imbalanced impairment of inhibitory synaptic responses in tg mice using brain slice preparations. Somatosensory thalamocortical projection makes not only monosynaptic glutamatergic connections but also disynaptic GABAergic connections, which mediate feedforward inhibition, onto layer IV neurons. In tg mice, IPSC amplitudes recorded from layer IV pyramidal cells of the somatosensory cortex in response to thalamic stimulation became disproportionately reduced compared with EPSC amplitudes at later developmental stages (postnatal days 21–30). Similar results were obtained by local stimulation of layer IV pyramidal neurons. However, IPSC reduction was not seen in layer V pyramidal neurons of epileptic tg mice or in layer IV pyramidal neurons of younger tg mice before the onset of epilepsy (postnatal days 14–16). These results showed that the feedforward inhibition from the thalamus to layer IV neurons of the somatosensory cortex was severely impaired in tg mice and that the impairment of the inhibitory synaptic transmission was correlated to the onset of absence epilepsy.