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  Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures

Hammelmann, V., Stieglitz, M. S., Huelle, H., Le Meur, K., Kass, J., Bruemmer, M., et al. (2019). Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures. JCI Insight, 4(9): e126418. doi:10.1172/jci.insight.126418.

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 Creators:
Hammelmann, Verena1, Author
Stieglitz, Marc Sebastian1, Author
Huelle, Henrik1, Author
Le Meur, Karim1, Author
Kass, Jennifer1, Author
Bruemmer, Manuela1, Author
Gruner, Christian1, Author
Roetzer, Rene Dominik1, Author
Fenske, Stefanie1, Author
Hartmann, Jana1, Author
Zott, Benedikt1, Author
Luthi, Anita1, Author
Spahn, Saskia1, Author
Moser, Markus2, Author              
Isbrandt, Dirk1, Author
Ludwig, Andreas1, Author
Konnerth, Arthur1, Author
Wahl-Schott, Christian1, Author
Biel, Martin1, Author
Affiliations:
1external, ou_persistent22              
2Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              

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Free keywords: ACTIVATED CATION CHANNELS; NUCLEOTIDE-GATED CHANNEL; IN-VIVO; PROTEIN-KINASE; ION CHANNELS; MODULATION; NEURONS; RAT; EPILEPSY; CORTEXResearch & Experimental Medicine;
 Abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually gated channels that are operated by voltage and by neurotransmitters via the cAMP system. cAMP-dependent HCN regulation has been proposed to play a key role in regulating circuit behavior in the thalamus. By analyzing a knockin mouse model (HCN2EA), in which binding of cAMP to HCN2 was abolished by 2 amino acid exchanges (R591E, T592A), we found that cAMP gating of HCN2 is essential for regulating the transition between the burst and tonic modes of firing in thalamic dorsal-lateral geniculate (dLGN) and ventrobasal (VB) nuclei. HCN2EA mice display impaired visual learning, generalized seizures of thalamic origin, and altered NREM sleep properties. VB-specific deletion of HCN2, but not of HCN4, also induced these generalized seizures of the absence type, corroborating a key role of HCN2 in this particular nucleus for controlling consciousness. Together, our data define distinct pathological phenotypes resulting from the loss of cAMP-mediated gating of a neuronal HCN channel.

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Language(s): eng - English
 Dates: 2019
 Publication Status: Published online
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: JCI Insight
Source Genre: Journal
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Publ. Info: 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA : AMER SOC CLINICAL INVESTIGATION INC
Pages: - Volume / Issue: 4 (9) Sequence Number: e126418 Start / End Page: - Identifier: -