Hammelmann, Verena, Stieglitz, Marc Sebastian, Huelle, Henrik, Le Meur, Karim, Kass, Jennifer, Bruemmer, Manuela, Gruner, Christian, Roetzer, Rene Dominik, Fenske, Stefanie, Hartmann, Jana ORCID: 0000-0002-1033-7104, Zott, Benedikt ORCID: 0000-0003-4537-7381, Luthi, Anita, Spahn, Saskia, Moser, Markus, Isbrandt, Dirk, Ludwig, Andreas, Konnerth, Arthur, Wahl-Schott, Christian and Biel, Martin ORCID: 0000-0002-9974-3052 (2019). Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures. JCI Insight, 4 (9). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hammelmann, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stieglitz, Marc SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huelle, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le Meur, KarimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kass, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruemmer, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruner, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roetzer, Rene DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fenske, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartmann, JanaUNSPECIFIEDorcid.org/0000-0002-1033-7104UNSPECIFIED
Zott, BenediktUNSPECIFIEDorcid.org/0000-0003-4537-7381UNSPECIFIED
Luthi, AnitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spahn, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moser, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isbrandt, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konnerth, ArthurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wahl-Schott, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biel, MartinUNSPECIFIEDorcid.org/0000-0002-9974-3052UNSPECIFIED
URN: urn:nbn:de:hbz:38-148625
DOI: 10.1172/jci.insight.126418
Journal or Publication Title: JCI Insight
Volume: 4
Number: 9
Date: 2019
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 2379-3708
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACTIVATED CATION CHANNELS; NUCLEOTIDE-GATED CHANNEL; IN-VIVO; PROTEIN-KINASE; ION CHANNELS; MODULATION; NEURONS; RAT; EPILEPSY; CORTEXMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14862

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