The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits

Department of Neurosciences, Medical Faculty, CMU, 1211 Geneva 4, Switzerland.
Neurobiology of Disease (Impact Factor: 5.08). 01/2006; 20(3):799-804. DOI: 10.1016/j.nbd.2005.05.013
Source: PubMed


Mutations in nAChRs are found in a rare form of nocturnal frontal lobe epilepsy (ADNFLE). Previously, some nAChR mutations have been described that are associated with additional neurological features such as psychiatric disorders or cognitive defects. Here, we report a new CHRNB2 mutation located in transmembrane region 3 (M3), outside the known ADNFLE mutation cluster. The CHRNB2 mutation I312M, which occurred de novo in twins, markedly increases the receptor's sensitivity to acetylcholine. Phenotypically, the mutation is associated not only with typical ADNFLE, but also with distinct deficits in memory. The cognitive problems are most obvious in tasks requiring the organization and storage of verbal information.

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    • "Moreover, a heterozygous missense I1287N of CHRNA2 was described in a pedigree where the phenotype of affected individuals was comparable to ADNFLE (Aridon et al., 2006). All of the identified ADNFLE mutations were heterozygous and within the nAChR gating regulator or pore region (Wonnacott, 1997; Combi et al., 2004; Bertrand et al., 2005) and dysfunction of the corresponding channels have been demonstrated in vitro. "
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    ABSTRACT: We generated a transgenic rat strain with a missense mutation in V286L (V286L-TG), in the gene encoding the neuronal nicotinic acetylcholine receptor β2 subunit (CHRNB2) found in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To confirm that V286L-TG rats exhibit seizures similar to those observed in humans, gene expression patterns and behavioral phenotypes were analyzed. In situ hybridization using a V286L Chrnb2-selective probe indicated that the transgene was expressed at higher levels in the cortex, hippocampus, and cerebellum of V286L-TG than wild-type littermates (non-TG). Spontaneous epileptic seizures with ictal discharges in electroencephalograms were detected in 45% of V286L-TG rats and the frequency of seizures was 0.73 times a week. This seizure type is similar to "paroxysmal arousals" that are observed in human ADNFLE. V286L-TG rats displayed nicotine-induced abnormal motor activity including seizures in comparison to non-TGs. Response time following nicotine administration occurred faster in V286L-TG than in non-TG rats. V286L-TG rats demonstrated spontaneous epileptic seizures, which are similar to human ADNFLE, and also showed a higher sensitivity to nicotine administration. Thus, the V286L-TG rat model could be a valuable tool for developing novel mechanism-driven treatment strategies for epilepsy and provide a better understanding of ADNFLE. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Neuroscience Research 06/2015; DOI:10.1016/j.neures.2015.06.003 · 1.94 Impact Factor
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    • "Interest for nAChR in several epileptic syndromes previously considered “idiopathic” was rekindled by the finding that altered functional properties of nAChR are implicated in the pathogenesis of nocturnal frontal lobe epilepsy (NFLE), and that seizures induced by nicotine in rodents model nAChR-related epilepsy. NFLE is linked with mutations of the α4 or β2 subunits [2], [3], [4], [5], [6], [7], the most abundantly expressed subunits in the CNS [8]. Though in human NFLE, or in genetically engineered mice that model the disease, functional properties of nAChRs are intimately altered, nicotine evokes seizures by over-activating a healthy system. "
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    ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.
    PLoS ONE 05/2013; 8(5):e64541. DOI:10.1371/journal.pone.0064541 · 3.23 Impact Factor
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    • "Mutations in the CHRNA4, CHRNB2, and CHRNA2 genes respectively encoding the α4, β2, and α2 subunits of the neuronal nicotinic acetylcholine receptor (nAChR) have been reported in less than a quarter of families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [4]. Mutations in CHRNA4 and CHRNB2 have been found even in sporadic cases [6] [7] [8] [9] [10] [11] [12]. "
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    ABSTRACT: The beneficial effect of nicotine has been reported in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) patients, but not tested in sporadic cases. Recently, a nicotine defect in the arousal pathway has been hypothesized even in sporadic NFLE patients and their relatives. This case-control family study was designed to test whether NFLE subjects were more likely to use tobacco than controls, as an indirect marker of cholinergic arousal system dysregulation. At least four relatives were included for each NFLE proband and control. Each subject was questioned about tobacco habits; 434 individuals were recruited. Moreover, we compared NFLE patients with age- and sex-matched controls to determine whether they are more likely to use tobacco. We found a slightly higher trend of tobacco use in NFLE probands compared to that in control subjects; we did not find any significant difference in the distribution of tobacco use among NFLE group compared to that in the control group.
    Epilepsy & Behavior 12/2012; 26(1). DOI:10.1016/j.yebeh.2012.10.014 · 2.26 Impact Factor
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