Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice.
Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice.
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异位 HCN4 表达驱动小鼠 mTOR 依赖性癫痫
DOI：
10.1126/scitranslmed.abc1492
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发表时间：
2020-11-18
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
局灶性皮质畸形（FCM）与癫痫之间的因果关系已被广泛接受，特别是在局灶性皮质发育不良II型（FCDII）和结节性硬化症（TSC）患者中。然而，癫痫发作的机制仍不清楚。利用TSC-和fcdii相关的FCM小鼠模型，我们发现FCM神经元通过异常表达超极化激活的环核苷酸门控钾通道异构体4 （HCN4）负责癫痫发作活动，而这种异构体在出生后通常不存在于皮质锥体神经元中。相对于其他亚型，增加细胞内cAMP浓度优先影响HCN4门控，可驱动FCM神经元的重复放电，但不控制锥体神经元。异位HCN4表达依赖于雷帕霉素（mTOR）的机制靶点，在癫痫发作之前，并且在TSC和FCDII患者切除的组织中的病变神经元中也发现。最后，在小鼠模型中，阻断FCM神经元中的HCN4通道活性可以预防癫痫。这些发现表明HCN4在癫痫发作中起主要作用，并确定了TSC和FCDII中camp依赖的癫痫发作机制。此外，HCN4在FCM神经元中的独特表达表明，针对HCN4的基因治疗可能有效减少FCDII或TSC的癫痫发作。由于病变神经元中HCN4通道的异位表达，camp依赖机制介导mTOR疾病中的癫痫发作。
The causative link between focal cortical malformations (FCM) and epilepsy is well-accepted, especially among patients with focal cortical dysplasia type II (FCDII) and tuberous sclerosis complex (TSC). However, the mechanisms underlying seizures remain unclear. Using a mouse model of TSC- and FCDII-associated FCM, we showed that FCM neurons were responsible for seizure activity via their unexpected abnormal expression of the hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4), which is normally not present in cortical pyramidal neurons after birth. Increasing intracellular cAMP concentrations, which preferentially affects HCN4 gating relative to the other isoforms, drove repetitive firing of FCM neurons but not control pyramidal neurons. Ectopic HCN4 expression was dependent on the mechanistic target of rapamycin (mTOR), preceded the onset of seizures, and was also found in diseased neurons in tissue resected from patients with TSC and FCDII. Finally, blocking HCN4 channel activity in FCM neurons prevented epilepsy in the mouse model. These findings suggest that HCN4 play a main role in seizure and identify a cAMP-dependent seizure mechanism in TSC and FCDII. Furthermore, the unique expression of HCN4 exclusively in FCM neurons suggests that gene therapy targeting HCN4 might be effective in reducing seizures in FCDII or TSC. A cAMP-dependent mechanism mediates seizures in mTOR disorders due to the ectopic expression of HCN4 channels in diseased neurons.
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影响因子：
2.7
作者：
Crino, Peter B.
通讯作者：
Crino, Peter B.
影响因子：
5.3
作者：
Brewster, A;Bender, RA;Baram, TZ
通讯作者：
Baram, TZ
影响因子：
4.8
作者：
Campostrini G;DiFrancesco JC;Castellotti B;Milanesi R;Gnecchi-Ruscone T;Bonzanni M;Bucchi A;Baruscotti M;Ferrarese C;Franceschetti S;Canafoglia L;Ragona F;Freri E;Labate A;Gambardella A;Costa C;Gellera C;Granata T;Barbuti A;DiFrancesco D
通讯作者：
DiFrancesco D
影响因子：
5.3
作者：
Grzelka K;Kurowski P;Gawlak M;Szulczyk P
通讯作者：
Szulczyk P
影响因子：
3.3
作者：
Abbas, S. Y.;Ying, S. W.;Goldstein, P. A.
通讯作者：
Goldstein, P. A.