Research ArticleEpilepsy

Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice

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Science Translational Medicine  18 Nov 2020:
Vol. 12, Issue 570, eabc1492
DOI: 10.1126/scitranslmed.abc1492

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Out of place channels drive seizures

Focal cortical malformations (FCMs) develop in a group of diseases caused by mutations in the mTOR pathway. Patients often develop pharmacoresistant epilepsy; however, the molecular mechanisms underlying seizure occurrence are not completely understood. Now, Hsieh et al. performed in vitro and in vivo studies in a mouse model of FCM to understand the mechanism of seizure generation. The authors showed that ectopic HCN4 channels expressed in FCM neurons were responsible for seizure generation by depolarizing the resting membrane potential. Expression analysis in cortical tissue from patients with FCM showed increased expression of HCN4, suggesting that HCN4 could be targeted for treating seizures in patients with FCM.

Abstract

The causative link between focal cortical malformations (FCMs) 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. Last, 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.

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