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Ectopic HCN4 expression drives mTOR-dependent epilepsy

Lawrence S. Hsieh, John H. Wen, Lena H. Nguyen, Longbo Zhang, Juan Torres-Reveron, Dennis D. Spencer, View ORCID ProfileAngélique Bordey
doi: https://doi.org/10.1101/853820
Lawrence S. Hsieh
1Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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John H. Wen
1Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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Lena H. Nguyen
1Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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Longbo Zhang
1Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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Juan Torres-Reveron
1Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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Dennis D. Spencer
1Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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Angélique Bordey
1Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
2Department of Cellular & Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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  • ORCID record for Angélique Bordey
  • For correspondence: angelique.bordey@yale.edu
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Abstract

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 show that FCM neurons are 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 levels, which preferentially affects HCN4 gating relative to the other isoforms, drove repetitive firing of FCM neurons but not that of control pyramidal neurons. Ectopic HCN4 expression was mTOR-dependent, preceded the onset of seizures, and was also found in diseased neurons in tissue resected for epilepsy treatment from TSC and FCDII patients. Finally, blocking HCN4 channel activity in FCM neurons prevented epilepsy in mice. These findings that demonstrate HCN4 acquisition as seizure-genic, identify a novel cAMP-dependent seizure mechanism in TSC and FCDII. Furthermore, the unique expression of HCN4 exclusively in FCM neurons provides opportunities for using HCN4 as a gene therapy target to treat epilepsy in individuals with FCDII or TSC.

One Sentence Summary Our data provide a novel cAMP-dependent mechanism of seizure initiation in focal cortical dysplasia and tuberous sclerosis complex due to the unexpected ectopic expression of HCN4 channels only in diseased neurons. HCN4 channels are thus promising candidates for gene therapy to treat epilepsy generated by mTOR-driven focal malformations.

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Posted November 24, 2019.
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Ectopic HCN4 expression drives mTOR-dependent epilepsy
Lawrence S. Hsieh, John H. Wen, Lena H. Nguyen, Longbo Zhang, Juan Torres-Reveron, Dennis D. Spencer, Angélique Bordey
bioRxiv 853820; doi: https://doi.org/10.1101/853820
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Ectopic HCN4 expression drives mTOR-dependent epilepsy
Lawrence S. Hsieh, John H. Wen, Lena H. Nguyen, Longbo Zhang, Juan Torres-Reveron, Dennis D. Spencer, Angélique Bordey
bioRxiv 853820; doi: https://doi.org/10.1101/853820

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