Impaired Regulation of Thalamic Pacemaker Channels through an Imbalance of Subunit Expression in Absence Epilepsy

Budde, Thomas; Caputi, Luigi; Kanyshkova, Tatyana; R, Staak; Abrahamczik, Christian; Munsch, Thomas; Pape, H.

doi:10.1523/jneurosci.2590-05.2005

Cited by 105 publications

(137 citation statements)

References 61 publications

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“…Reduced expression of NR1 subunits of NMDA receptors in the somatosensory cortex in comparison to non-epileptic ACI rats both at 3 and 6 months of age (van de BovenkampJanssen et al, 2006) Lower expression of the NR2B subunit of the NMDA receptors in both 2-month-old and 6-month-old WAG/Rij rats in different layers of the somatosensory cortex in comparison to Wistar rats of the same age (Karimzadeh et al, 2013) AMPA-GluA4 subunit density is lower in WAG/Rij rats than in ACI rats in S1po layers independently from age and seizure development GluA2 subunits are not expressed around cell bodies in thalamic nuclei with the exception of the NRT, whereas, they are widely expressed in the two cortical sites examined (S1po and the forelimb region of the primary somatosensory cortex (Citraro et al, 2006b) Reduced expression and function of mGlu5 receptors in the thalamus has been observed in pre-epileptic WAG/Rij rats, while an increased receptor expression in the sensorimotor cortex was described (D'Amore et al, 2013) Ion Channels Altered HCN channel expression and cAMP sensitivity of I h has been shown in WAG/Rij rats in the postnatal age continuing into the chronic epilepsy state; HCN1 channel expression decreases, mainly in the dendrites of cortical layer V pyramidal neurons that occurs temporally before the developmental onset of SWDs, and at a cellular level plays a direct role in promoting dendritic Ca 2+ electrogenesis and burst firing (Budde et al, 2005;Kuisle et al, 2006) …”

Section: Glutamatementioning

confidence: 99%

“…Altered HCN channel expression and cAMP sensitivity of I h has been shown in WAG/Rij rats in the postnatal age continuing into the chronic epilepsy state (Budde et al, 2005;Kuisle et al, 2006). The I h -dependent changes in active and passive membrane properties become significant at 3 months of age and persist into adulthood (Budde et al, 2005).…”

Section: Ion Channelsmentioning

confidence: 99%

“…The I h -dependent changes in active and passive membrane properties become significant at 3 months of age and persist into adulthood (Budde et al, 2005). Although the resulting alterations of I h current density, voltage-dependency, current kinetics, and cAMPdependent modulation are mostly compensated in older animals (Kuisle et al, 2006), early HCN channel dysregulation has been suggested to contribute to the development of the epileptic phenotype (Blumenfeld et al, 2008;Kanyshkova et al, 2012) and therefore they might be relevant to absence epileptogenesis.…”

Section: Ion Channelsmentioning

confidence: 99%

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Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Russo

Citraro

Constanti³

et al. 2016

Neuroscience & Biobehavioral Reviews

128

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Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development.Neuroscience and Biobehavioral Reviews http://dx.doi.org/10. 1016/j.neubiorev.2016.09.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current-deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial "insult" responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then nongenetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling.

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Section: Glutamatementioning

confidence: 99%

Section: Ion Channelsmentioning

confidence: 99%

Section: Ion Channelsmentioning

confidence: 99%

See 1 more Smart Citation

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Russo

Citraro

Constanti³

et al. 2016

Neuroscience & Biobehavioral Reviews

128

View full text Add to dashboard Cite

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“…163 The WAG/Rij rat model of ab-sence epilepsy shows a loss of HCN1 function in the cortex 164 (possibly linked to the origin of cortical spikeand-wave discharges) but enhanced HCN1 expression in the thalamus. 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.…”

Section: Hcn Channelsmentioning

confidence: 99%

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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“…PKA sets the classic example of autoinhibition in a cAMP receptor, but HCN channels differ from PKA in key respects. Whereas PKA catalyses a metabolic modification (phosphorylation), HCN channels produce a time-resolved electrical response in rhythmically firing cells (20,31). Oscillatory properties are sensitive to channel kinetics just as much as to channel thermodynamics, so fine-tuned control of HCN channel kinetics could have an adaptive benefit in evolution.…”

Section: Weakened Open-state Trapping In C-1 Does Not Indicate An Altmentioning

confidence: 99%

Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating

Wicks

Wong²,

Sun³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Voltage gating of hyperpolarization-activated cation (HCN) channels is potentiated by direct binding of cAMP to a cytoplasmic cAMP-sensing domain (CSD). When unliganded, the CSD inhibits hyperpolarization-dependent opening of the HCN channel gate; cAMP binding relieves this autoinhibition so that opening becomes more favorable thermodynamically. This autoinhibition-relief mechanism is conserved with that of several other cyclic nucleotide receptors using the same ligand-binding fold. Besides its thermodynamic effect, cAMP also modulates the depolarization-dependent deactivation rate by kinetically that is formed by mode shift after prolonged hyperpolarization activation. This hysteretic activation-deactivation cycle is preserved by CSD substitution, but the change in deactivation kinetics of the liganded channel resulting from CSD substitution is not correlated with the change in autoinhibition properties. Thus the liganded and the unliganded forms of the CSD respectively provide the structural determinants for open-state trapping and autoinhibition, such that two distinct mechanisms for cAMP regulation can operate in one receptor. HCN channels are tetramers of homologous subunits; each subunit has six membrane-spanning helices (S1-S6) homologous to those of voltage-gated potassium channels, with a voltagesensing domain in S1-S4 (4). Hyperpolarization drives inward movement of the positively charged S4 (5), which is coupled to opening of the pore gate formed by the cytoplasmic C-terminal ends of the four S6 helices in the tetramer (6). S6 in each subunit is followed by an 80-residue "C-linker" with an unusual multihelix fold (7), then the cAMP-binding fold and a poorly conserved "extreme C-terminal" region. The C-linker and cAMP-binding fold together can be viewed as one "cAMP-sensing domain" (CSD; see Fig. 1A, Top), based on domain stability (7) and the C-linker's functional importance (8).Cyclic AMP binding potentiates hyperpolarization-dependent activation of HCN channels (9). That is, cAMP increases thermodynamic stability of the open channel relative to the closed channel, so that the voltage needed for half-maximal activation (V 1∕2 ) becomes less negative. A similar V 1∕2 shift can be produced by deleting the CSD through enzymatic or genetic truncation (10, 11). This establishes a classical autoinhibition mechanism (12) as the basis for cAMP regulation of HCN channels, in analogy with PKA (13) and EPAC (14). Thus the unliganded ("apo") CSD inhibits an intrinsic activity of the channel, and the liganded ("holo") form of the CSD has weakened or nonexistent capability for this inhibition, so that cAMP binding mimics CSD deletion. Because the autoinhibition-relief model attributes specific regulatory function to the apo CSD rather than the holo CSD, we introduce the designation "apo-driven" for this mechanism type. In a "holo-driven" mechanism, by contrast, the presence of the CSD with bound ligand would be required for a particular HCN channel structure that achieves optimal activation. A holodriven mechanis...

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Impaired Regulation of Thalamic Pacemaker Channels through an Imbalance of Subunit Expression in Absence Epilepsy

Cited by 105 publications

References 61 publications

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

Molecular Targets for Antiepileptic Drug Development

Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating

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