Developmental Febrile Seizures Modulate Hippocampal Gene Expression of Hyperpolarization-Activated Channels in an Isoform- and Cell-Specific Manner

Abstract

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.

Neuropeptide Y: Potential role in recurrent developmental seizures

“…The threshold temperatures generating experimental FS are close to those required for FS in normal children [14]. As indicated by seizure behavior and confirmed with electrophysiological recordings from multiple brain sites, these seizures are limbic and the behavior during the seizures is reproducible and stereotyped [10,18,32]. Seizure duration can be tightly controlled in the model.…”

“…In order to study the consequences of complex FS, and thus to gain a better understanding of their potential contribution to human epilepsy, an animal model of FS was established in our laboratory [10,18,19,32,33,73]. In this model, experimental FS are induced in rat pups on postnatal days 10 or 11, an age that corresponds to the hippocampal developmental stage at which human infants are most susceptible to febrile seizures (see comparison of developmental milestones in humans and rodent hippocampus in [4]).…”

“…This may be due in part to profound and long-lasting changes in the expression of the hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel genes after FS [12,18,19,66]. These data together suggest that prolonged experimental FS induce plastic processes in the brain that render the neuronal network hyperexcitable [18,19,23,24,32,33].…”

Molecular Targets for Antiepileptic Drug Development

“…165 In addition, changes in I h and in HCN subunit expression have been observed in epileptogenesis. Following febrile seizures in infant rodents, there is a prolonged increase in I h , 166,167 but after kainate seizures there is a reduction in I h in entorhinal cortex layer III neurons. 168 I h is an attractive potential AED target for different types of epilepsy.…”

Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures

“…Short-term modulation of HCN channel function is mediated by cAMP, influencing channel kinetics and voltage dependent activation curves (DiFrancesco, 1993;Waigner et al, 2001). Recently, long-term modulation of the properties of I h currents has been suggested to result from regulated changes in channel subunit expression (Bräuer et al, 2001;Brewster et al, 2002;Santoro and Baram, 2003).…”