Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice

• DOI: 10.1126/scitranslmed.abc1492
• Publication Date: 2020-11-19T00:23:47Z
• Authors: Lawrence S. Hsieh; John H. Wen; Lena H. Nguyen; Longbo Zhang; Stephanie A. Getz; Juan Torres-Reveron; Ying Wang; Dennis D. Spencer; Angélique Bordey
• Keywords: Ectopic expression

The causative link between focal cortical malformations (FCMs) and epilepsy is well accepted, especially among patients with dysplasia type II (FCDII) tuberous sclerosis complex (TSC). However, the mechanisms underlying seizures remain unclear. Using a mouse model of TSC- FCDII-associated FCM, we showed that FCM neurons were responsible for seizure activity via their unexpected abnormal expression hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4), which normally not present in pyramidal after birth. Increasing intracellular cAMP concentrations, preferentially affects HCN4 gating relative to other isoforms, drove repetitive firing but control neurons. Ectopic was dependent on mechanistic target rapamycin (mTOR), preceded onset seizures, also found diseased tissue resected from TSC FCDII. Last, blocking prevented model. These findings suggest play main role identify cAMP-dependent mechanism Furthermore, unique exclusively suggests gene therapy targeting might be effective reducing FCDII or TSC.