Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability

Chen, Kang; Aradi, Ildikó; Thon, Niklas; Eghbal-Ahmadi, Mariam; Baram, Tallie Z.; Soltész, Iván

doi:10.1038/85480

Cited by 395 publications

(383 citation statements)

References 45 publications

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“…These findings are in line with the duration of transcriptional dysregulation of the HCN channel isoform expression: Reduced HCN1 mRNA levels endured for at least 3 months after 'febrile' seizures, but not in rats subjected to kainic acid seizures early in life (Brewster et al, 2002). This enduring increase of HCN channel heteromerization after 'febrile' seizures was associated with alterations of I h that promote hippocampal hyperexcitability (Chen et al, 2001a;Santoro and Baram, 2003). While it is tempting to speculate that heteromeric channels underlie the modified I h , other potential mechanisms might be involved.…”

Section: Seizure-evoked Co-association Of Hcn1/hcn2 Is Not Model-specsupporting

confidence: 66%

“…Differential regulation of HCN1 and HCN2 mRNA expression has been found in pathological states (Bender et al, 2003;Bräuer et al, 2001;Brewster et al, 2002), including experimental febrile and kainate-induced seizures, and has been associated with altered properties of the I h (Chen et al, 2001a). Interestingly, the properties of I h after experimental febrile seizures resembled neither those of heterologously expressed homomeric HCN1 or HCN2 channels, nor their arithmetic intermediates (Chen et al, 2001a,b;Ulens and Tytgat, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

Brewster

Bernard

Gall

et al. 2005

Neurobiology of Disease

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112

119

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate hyperpolarizationactivated currents (I h ). In hippocampus, these currents contribute greatly to intrinsic cellular properties and synchronized neuronal activity. The kinetic and gating properties of HCN-mediated currents are largely determined by the type of subunits-for example, HCN1 and HCN2-that assemble to form homomeric channels. Recently, functional heteromeric HCN channels have been described in vitro, further enlarging the potential I h repertoire of individual neurons. Because these heteromeric HCN channels may promote hippocampal hyperexcitability and the development of epilepsy, understanding the mechanisms governing their formation is of major clinical relevance. Here, we find that developmental seizures promote co-assembly of hippocampal HCN1/HCN2 heteromeric channels, in a duration-dependent manner. Long-lasting heteromerization was found selectively after seizures that provoked persistent hippocampal hyperexcitability. The mechanism for this enhanced heteromerization may involve increased relative abundance of HCN2-type subunits relative to the HCN1 isoform at both mRNA and protein levels. These data suggest that heteromeric HCN channels may provide molecular targets for intervention in the epileptogenic process.

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Section: Seizure-evoked Co-association Of Hcn1/hcn2 Is Not Model-specsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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

Brewster

Bernard

Gall

et al. 2005

Neurobiology of Disease

Self Cite

112

119

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“…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.…”

Section: Hcn Channelsmentioning

confidence: 98%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…However, the inhibition reported by Chen et al (1999) was likely derived from whole cell somatic patch, and not from dendritic membrane. In addition, based on a model simulating both intracellular and field responses of CA1 pyramidal cells (Leung and Peloquin, 2006), while a change in the H-current characteristics after seizures may alter spike excitability (Chen et al, 2001), it does not account for the difference in heterosynaptic paired pulse response in seizure compared to control rats as shown in Fig. 5C (simulation data not shown).…”

Section: Long-lasting Loss Of Ca1 Proximal Dendritic Inhibition Aftermentioning

confidence: 99%

Loss of dendritic inhibition in the hippocampus after repeated early-life hyperthermic seizures in rats

Boyce

Leung

2013

Epilepsy Research

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"Loss of dendritic inhibition in the hippocampus after repeated early-life hyperthermic seizures in rats." (2013) Summary Seizures are relatively common in children and are a risk factor for subsequent temporal lobe epilepsy. To investigate whether early-life seizures themselves are detrimental to the proper function of the adult brain, we studied whether dendritic excitation and inhibition in the hippocampus of adult rats were altered after hyperthermia-induced seizures in immature rats. In particular, we hypothesized that apical dendritic inhibition in hippocampal CA1 pyramidal cells would be disrupted following hyperthermia-induced seizures in early life. Seizure rats were given three hyperthermia-induced seizures per day for three days from postnatal day (PND) 13 to 15; control rats were handled similarly but not heated. At PND 65-75, paired-pulse inhibition in area CA1 was evaluated under urethane anesthesia, using CA3 and medial perforant path (MPP) stimulation to excite the proximal and distal apical-dendrites, respectively, and the evoked field potentials were analyzed by current source density. There was no difference in the CA1 response to single-pulse stimulation of CA3 or MPP. In control rats, a high-intensity CA3 stimulus inhibited a subsequent MPP-evoked CA1 distal dendritic excitatory sink, and the inhibition at 150-200 ms was blocked by a GABA B receptor antagonist. Seizure as compared to control rats showed a decrease in a CA3-evoked inhibition of the CA1 distal dendritic excitation, 30-400 ms after the CA3 stimulus. In addition, seizure as compared to control rats showed a reduced early (20-80 ms) inhibition of a CA1 mid-apical dendritic sink following paired-pulse CA3 stimulation. In conclusion, long-term alterations in dendritic inhibition in CA1 were found following early-life seizures.

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Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability

Cited by 395 publications

References 45 publications

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

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

Molecular Targets for Antiepileptic Drug Development

Loss of dendritic inhibition in the hippocampus after repeated early-life hyperthermic seizures in rats

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