| First Author | Hammelmann V | Year | 2019 |
| Journal | JCI Insight | Volume | 4 |
| Issue | 9 | PubMed ID | 31045576 |
| Mgi Jnum | J:298057 | Mgi Id | MGI:6457191 |
| Doi | 10.1172/jci.insight.126418 | Citation | Hammelmann V, et al. (2019) Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures. JCI Insight 4(9) |
| abstractText | 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. |
