Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis.
Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis.
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DOI：
10.1523/jneurosci.1531-09.2009
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发表时间：
2009-09-02
期刊：
影响因子：
--
通讯作者：
Shah MM
中科院分区：
文献类型：
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作者：
Huang Z;Walker MC;Shah MM
内嗅皮层（EC）和海马锥体细胞树突中的HCN 1可塑性是颞叶癫痫（TLE）的显著特征。然而，其重要性仍未确定。我们证明，成年HCN 1基因敲除小鼠对红藻氨酸诱导的癫痫发作更敏感。在用抗惊厥药终止这些之后，小鼠也以比其野生型同窝小鼠显著更快的速率发生自发性行为癫痫发作。这种更大的癫痫易感性伴随着HCN 1 −/− EC第III层神经元自发活动的增加。树突状Ih也被消融。因此，HCN 1 −/−树突更容易兴奋，尽管具有更高的超极化静息膜电位（RMP）。此外，兴奋性突触后电位（EPSP）的整合大大增强，以至于在正常RMP下，50 Hz的EPSP序列在HCN 1 −/−神经元中产生动作电位。由于这种增强的锥体细胞兴奋性，HCN 1 −/−神经元的自发EPSC频率大大高于野生型，导致正常兴奋性和抑制性突触活动之间的不平衡。这些结果表明，树突状HCN通道可能在调节皮质锥体细胞兴奋性中发挥关键作用。此外，这些发现表明，在癫痫发生过程中树突状HCN 1亚基表达的减少可能会促进疾病。
HCN1 plasticity in entorhinal cortical (EC) and hippocampal pyramidal cell dendrites is a salient feature of temporal lobe epilepsy (TLE). However, the significance remains undetermined. We demonstrate that adult HCN1 null mice are more susceptible to kainic acid induced seizures. Following termination of these with an anticonvulsant, the mice also developed spontaneous behavioural seizures at a significantly more rapid rate than their wildtype littermates. This greater seizure susceptibility was accompanied by increased spontaneous activity in HCN1−/− EC layer III neurons. Dendritic Ih in these neurons was ablated, too. Consequentially, HCN1−/− dendrites were more excitable, despite having significantly more hyperpolarized resting membrane potentials (RMP). In addition, the integration of excitatory post-synaptic potentials (EPSPs) was enhanced considerably such that at normal RMP, a 50 Hz train of EPSPs produced action potentials in HCN1−/− neurons. As a result of this enhanced pyramidal cell excitability, spontaneous EPSC frequency onto HCN1−/− neurons was considerably greater than that onto wildtypes, causing an imbalance between normal excitatory and inhibitory synaptic activity. These results suggest that dendritic HCN channels are likely to play a critical role in regulating cortical pyramidal cell excitability. Further, these findings suggest that the reduction in dendritic HCN1 subunit expression during epileptogenesis is likely to facilitate the disorder.