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• W2275365306 abstract "RATIONALE: The Cav2.3 (R-type) voltage-gated calcium channel represents the most enigmatic of all voltage-gated calcium channels due to its pharmacoresistance, mixedcharacteristics of high voltage-activated and low voltage-activated calcium channels and relatively low expression levels. Lamotrigine (LTG) is a modern antiepileptic drughowever, its mechanism of action has yet to be fully understood, as it is known to modulate several ion channels and other targets. In heterologous systems, LTG inhibitsCav2.3 (R-type) calcium currents, which contribute to kainic-acid (KA)–induced epilepsy in vivo. LTG has been suggested to increase the risk of sudden unexpected death inepilepsy (SUDEP), in which cardiac and respiratory mechanisms are proposed to be involved. In addition to the higher risk of SUDEP during sleep, epileptic patients are athigher risk of seizures during sleep, especially during slow wave sleep (SWS). The bidirectional relationship between sleep and epilepsy has long been acknowledged,however it remains far from understood. AIM: The goal of the present project was to perform an in depth investigation of the role of R-type signaling in the epileptic brain and heart, by analyzing its contribution toexperimental epilepsy, antiepileptic pharmacotherapy and sleep. METHODS: In the first study we compared the effects of LTG to two other AEDs (Topiramate and Lacosamide) in Cav2.3-deficient mice and controls on KA-induced seizures. Behavioral seizure rating and quantitative electrocorticography were performed after KA induced epilepsy, as well as immunohistochemistry and western blot analysis of Cav2.3 expression in the brain. In the second study we investigated cardiac parameters during KA-induced epilepsy and LTG treatment in awake and sleeping C57Bl6 mice. Continuous electrocardiograms and electrocorticograms were collected telemetrically from freely moving mice, and time- and frequency-domain analysis performed on theelectrocardiograms. In the third study, we analyzed sleep architecture in Cav2.3-deficient and control mice also using radiotelemetric electrocorticography and electromyography during spontaneous and urethane-induced sleep. RESULTS: LTG treatment displayed no antiepileptic potency in Cav2.3-deficient mice, but contrarily significantly aggravated seizures and increased neurodegeneration in the CA1 region of the hippocampus as well as increasing ultra-high frequency oscillations(ripples) known to be associated with seizure generation. This effect was specific to LTG in Cav2.3-deficient mice, as the two other AEDs tested - one with and one without Cav2.3 inhibiting capacity- did not aggravate seizures. In our second study we found LTG to alter autonomous nervous control of the heart during SWS after induction of chronicepilepsy promoting sympatho-vagal imbalance. Furthermore, we found LTG to increase the squared-coefficient of variation of the heart rate during SWS, but not duringwakefulness. Our third study was able to demonstrate, that ablation of Cav2.3 robustly impacts sleep architecture, producing deficits in the amount and depth of SWS.Interestingly, although Cav2.3 mice sleep less and display shorter SWS phases, they do not compensate for this deficit by increasing sleep depth, pointing to disturbances in sleephomeostasis. DISCUSSION: We provide first in vivo evidence for a crucial role of R-type signaling in LTG pharmacology and shed light on a paradoxical effect of LTG in the absence of Cav2.3. LTG appears to promote ictal activity in Cav2.3-deficient mice by increasing high frequency components of seizures, resulting in increased neurotoxicity in the CA1. This paradoxical mechanism, possibly reflecting rebound hyperexcitation may be key inunderstanding LTG-induced seizure aggravation observed in patients. Furthermore, we find Cav2.3 to be a critical mediator of sleep homeostasis, potentially representing apivotal link between sleep and epilepsy. Cav2.3 has been shown to be crucial for bursting in the reticular thalamus, which underlies delta-rhythm during SWS and generation ofspike-and-wave discharges, the hallmark of absence epilepsy. Therefore, seizure resistance and SWS impairment of Cav2.3-deficient mice may be symptomatic ofimpairment of bursting in the thalamus and therefore of the generation and maintenance of highly synchronized slow rhythms. Remarkably, we found LTG to only affectautonomous control of the epileptic heart during SWS, possibly indicating a mechanism by which LTG could increase the risk for SUDEP. LTG-induced increased sympathetictone during SWS, may also reflect impaired SWS, found in LTG-treated patients and in our Cav2.3-deficient mice.CONCLUSION: Because Cav2.3-deficient mice display a subtle phenotype as oppposed to an obvious one, because of the expression of Cav2.3 in rhythmically active tissue and because of Cav2.3’s unique electrophysiological properties, it is conceivable that a general function of R-type currents is the “fine tuning” of oscillatory networks One may assume that a loss of “fine-tuning” in Cav2.3KO mice is only minimally noticeable under physiological conditions, but becomes evident in certain pathological conditions exerting a strain on an oscillatory network such as during experimentally induced epilepsy. This may explain how R-type signaling is crucial for sustaining physiological rhythmic activity of an entire network despite relatively low expression levels." @default.
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• W2275365306 date "2015-01-01" @default.
• W2275365306 modified "2023-09-27" @default.
• W2275365306 title "Mechanisms of the Cav2.3 Calcium Channel’s Role in Epileptogenesis and Antiepileptic Pharmacotherapy" @default.
• W2275365306 hasPublicationYear "2015" @default.
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