Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009952 (febrile convulsions)
 1,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Febrile seizures, in addition to being the most common seizure type of the developing human, may contribute to the generation of subsequent limbic epilepsy. Our previous work has demonstrated that prolonged experimental febrile seizures in the immature rat model increased hippocampal excitability long term, enhancing susceptibility to future seizures. The mechanisms for these profound proepileptogenic changes did not require cell death and were associated with long-term slowed kinetics of the hyperpolarization-activated depolarizing current (I(H)). Here we show that these seizures modulate the expression of genes encoding this current, the hyperpolarization-activated, cyclic nucleotide-gated channels (HCNs): In CA1 neurons expressing multiple HCN isoforms, the seizures induced a coordinated reduction of HCN1 mRNA and enhancement of HCN2 expression, thus altering the neuronal HCN phenotype. The seizure-induced augmentation of HCN2 expression involved CA3 in addition to CA1, whereas for HCN4, mRNA expression was not changed by the seizures in either hippocampal region. This isoform- and region-specific transcriptional regulation of the HCNs required neuronal activity rather than hyperthermia alone, correlated with seizure duration, and favored the formation of slow-kinetics HCN2-encoded channels. In summary, these data demonstrate a novel, activity-dependent transcriptional regulation of HCN molecules by developmental seizures. These changes result in long-lasting alteration of the HCN phenotype of specific hippocampal neuronal populations, with profound consequences on the excitability of the hippocampal network.
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PMID:Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform- and cell-specific manner. 1204 66

Persistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy, and generalized epilepsy animal models, as well as in patients with epilepsy. However, the role and importance of HCN1 down-regulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure-induction method used. Therefore, down-regulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor in seizure behavior.
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PMID:Increased seizure severity and seizure-related death in mice lacking HCN1 channels. 2038 28

Hyperpolarization-activated cyclic nucleotide-gated channels (HCN) can act as pacemakers in the brain making them strong candidates for driving aberrant hypersynchronous network activity seen in epilepsy. Transcriptional changes in HCN channels occur in several animal models of epilepsy. However, only recently have genetic studies demonstrated sequence variation in HCN1 and HCN2 genes associated with human epilepsy. These include a triple proline deletion in HCN2 that increases channel function and occurs more often in patients with febrile seizure syndromes. Other HCNx gene variants have been described in idiopathic generalized epilepsy although the functional consequence of these remains unclear. In this review we explore potential cellular and network mechanisms involving HCN channels in the genetic epilepsies. We suggest how new genetic sequencing technology, medium-throughput functional assays and the ability to develop syndrome-specific animal models will provide a more comprehensive understanding of how I(h) contributes to pathogenic mechanisms underlying human genetic epilepsy. We also discuss what is known about the pharmacological manipulation of HCN channels in the context of epilepsy and how this may help future efforts in developing HCN-channel-based therapy.
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PMID:HCN channelopathies: pathophysiology in genetic epilepsy and therapeutic implications. 2161 28