Tobacco habits modulate autosomal dominant nocturnal frontal lobe epilepsy (original) (raw)
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Neuropsychological disturbances in frontal lobe epilepsy due to mutated nicotinic receptors
Epilepsy & Behavior, 2009
Mutations in nicotinic receptor subunits have been identified in some families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Normal intelligence has currently been considered the rule, although anecdotal cases with intellectual disability have been reported. We aimed to evaluate the frequency and degree of neuropsychological disorders in ADNFLE associated with nicotinic receptor mutations by testing 11 subjects from four families with a comprehensive neuropsychological assessment. General intellectual function was below the normal range in 45% of the subjects. All were abnormal in one or more executive task. Memory was either more affected than executive functions or equally affected in two thirds of subjects, suggesting a frontotemporal pattern of cognitive impairment. Cognitive dysfunction appears to be an integral part of the broad phenotype of ADNFLE with nicotinic receptor mutations, a fact that has been underestimated until now. The cognitive disorder affects executive functions as well as memory in most subjects.
Molecular …, 2002
High doses of nicotine, the addictive component of tobacco, induce clonic-tonic seizures in animals. Pharmacological and biochemical data have suggested that ␣7-containing neuronal nicotinic receptors (nAChRs) contribute to these seizures. To study potential ␣7 contributions, we examined ␣7 subunits with a Leu250-to-Thr substitution in the channel domain, which creates a gain-of-function mutation. Previous studies have shown that mice homozygous for the ␣7 L250T mutation (T/T) die shortly after birth, but animals heterozygous for the mutation (ϩ/T) are viable and grow to adulthood. Hippocampal neurons from the ϩ/T mice exhibited altered ␣7-type currents with increased amplitudes and slower desensitization kinetics, confirming a partial gain of function for the ␣7 nAChR. We found that ϩ/T mice were more sensitive to the convulsant effects of nicotine compared with their wild-type (ϩ/ϩ) littermates. Furthermore, although their behavior was normal in basal conditions, ϩ/T mice showed a unique nicotine-induced phenotype, consisting of head-bobbing and paw-tapping movements. Increased sensitivity to nicotine-induced seizures occurred despite a 60% decline in brain ␣7 nAChR protein levels. There were no changes in the levels of ␣4, ␣5, ␣6, ␣7, 2, and 4 mRNA, or in [ 125 I]epibatidine and [ 3 H]nicotine binding between ϩ/T and ϩ/ϩ mice. Recent data from our laboratory show that ␣7-null mice maintain normal sensitivity to nicotine-induced seizures. Hence, these present findings suggest that alterations in the properties rather than absence of ␣7 nAChRs might affect the mechanisms underlying the convulsive properties of nicotine.
Molecular Pharmacology, 2002
High doses of nicotine, the addictive component of tobacco, induce clonic-tonic seizures in animals. Pharmacological and biochemical data have suggested that alpha 7-containing neuronal nicotinic receptors (nAChRs) contribute to these seizures. To study potential alpha 7 contributions, we examined alpha 7 subunits with a Leu250-to-Thr substitution in the channel domain, which creates a gain-of-function mutation. Previous studies have shown that mice homozygous for the alpha 7 L250T mutation (T/T) die shortly after birth, but animals heterozygous for the mutation (+/T) are viable and grow to adulthood. Hippocampal neurons from the +/T mice exhibited altered alpha 7-type currents with increased amplitudes and slower desensitization kinetics, confirming a partial gain of function for the alpha 7 nAChR. We found that +/T mice were more sensitive to the convulsant effects of nicotine compared with their wild-type (+/+) littermates. Furthermore, although their behavior was normal in basal conditions, +/T mice showed a unique nicotine-induced phenotype, consisting of head-bobbing and paw-tapping movements. Increased sensitivity to nicotine-induced seizures occurred despite a 60% decline in brain alpha 7 nAChR protein levels. There were no changes in the levels of alpha 4, alpha 5, alpha 6, alpha 7, beta 2, and beta 4 mRNA, or in [(125)I]epibatidine and [(3)H]nicotine binding between +/T and +/+ mice. Recent data from our laboratory show that alpha 7-null mice maintain normal sensitivity to nicotine-induced seizures. Hence, these present findings suggest that alterations in the properties rather than absence of alpha 7 nAChRs might affect the mechanisms underlying the convulsive properties of nicotine.
The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy
Frontiers in physiology, 2015
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a focal epilepsy with attacks typically arising in the frontal lobe during non-rapid eye movement (NREM) sleep. It is characterized by clusters of complex and stereotyped hypermotor seizures, frequently accompanied by sudden arousals. Cognitive and psychiatric symptoms may be also observed. Approximately 12% of the ADNFLE families carry mutations on genes coding for subunits of the heteromeric neuronal nicotinic receptors (nAChRs). This is consistent with the widespread expression of these receptors, particularly the α4β2(*) subtype, in the neocortex and thalamus. However, understanding how mutant nAChRs lead to partial frontal epilepsy is far from being straightforward because of the complexity of the cholinergic regulation in both developing and mature brains. The relation with the sleep-waking cycle must be also explained. We discuss some possible pathogenetic mechanisms in the light of recent advances about the nAChR...
Potential Role of the α4 and α6 Nicotinic Receptor Subunits in Regulating Nicotine-Induced Seizures
Journal of Pharmacology and Experimental Therapeutics, 2000
Several studies have shown that genetic factors influence sensitivity to nicotine-induced seizures in the mouse. We used recombinant inbred (RI) strains derived from the Long-Sleep (LS) and Short-Sleep (SS) mouse lines to assess the possibility that polymorphisms associated with one or more of the nicotinic receptors cosegregate with differential sensitivity to nicotine-induced seizures. Restriction fragment length polymorphisms (RFLPs) associated with the ␣2, ␣3, ␣4, ␣5, and ␣6 nicotinic receptors were identified in the LS and SS mouse lines, but the RI strains were polymorphic for only the ␣4 and ␣6 RFLPs. The RI strains were tested for sensitivity to nicotineinduced seizures. Strain and gender effects on seizure sensitivity were obtained as assessed by ED 50 values and latency to seizure. Those RI strains with the LS-like ␣4 RFLP were, on average, more sensitive to nicotine-induced seizures than were those RI strains with SS-like ␣4 RFLP. The ␣6 nicotine receptor may also play a role in modulating nicotine-induced seizures, but this effect is markedly influenced by gender. Females of the RI strains with the LS-like ␣6 RFLP were more sensitive to nicotine than were females of the strains with the SS-like ␣6 RFLP. Similar trends were seen in the males, but these trends were not significant. Thus, these strain differences may be due to polymorphisms associated with both the ␣4 and ␣6 nicotinic receptors, but gender also plays an important role in regulating sensitivity to nicotine-induced seizure.
Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy
European journal of nuclear medicine and molecular imaging, 2018
Mutations of cholinergic neuronal nicotinic receptors have been identified in the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), associated with changes on PET images using [F]-F-85380-A (F-A-85380), an α4β2 nicotinic receptor ligand. The aim of the present study was to evaluate potential changes in nicotinic receptor availability in other types of epilepsy. We included 34 male participants, 12 patients with idiopathic generalized epilepsy (IGE), 10 with non-lesional diurnal focal epilepsy, and 12 age-matched healthy controls. All patients underwent PET/CT using F-A-85380 and [F]-fluorodeoxyglucose (FDG), 3D T1 MRI and diffusion tensor imaging (DTI). F-A-85380 and FDG images were compared with the control group using a voxel-wise (SPM12) and a volumes of interest (VOI) analysis. In the group of patients with IGE, the voxel-wise and VOI analyses showed a significant increase of F-A-85380 ratio index of binding potential (BP, corresponding to the receptor availability) i...
Epilepsia, 2002
Summary: Twenty-four autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) probands were analyzed for the presence of V287L and V287M mutations in the CHRNB2 gene, which have been recently associated with the disease. In all patients, the involvement of the two additional loci reported as being associated with ADNFLE (CHRNA4 gene and chromosome 15q24 region) had been previously excluded. Mutational screening was performed by sequencing a polymerase chain reaction–amplified CHRNB2 DNA fragment, spanning the whole exon 5, which contains the V287L and V287M mutations and codes for ∼65% of the mature protein. In none of the patients were mutations in the analyzed region of CHRNB2 found. These data, obtained in the largest ADNFLE cohort so far analyzed, demonstrate the rarity of the identified CHRNB2 mutations in ADNFLE patients.
Journal of Neuroscience, 2007
We generated a mouse line harboring an autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) mutation: the alpha4 nicotinic receptor S248F knock-in strain. In this mouse, modest nicotine doses (1-2 mg/kg) elicit a novel behavior termed the dystonic arousal complex (DAC). The DAC includes stereotypical head movements, body jerking, and forelimb dystonia; these behaviors resemble some core features of ADNFLE. A marked Straub tail is an additional component of the DAC. Similar to attacks in ADNFLE, the DAC can be partially suppressed by the sodium channel blocker carbamazepine or by pre-exposure to a very low dose of nicotine (0.1 mg/kg). The DAC is centrally mediated, genetically highly penetrant, and, surprisingly, not associated with overt ictal electrical activity as assessed by (1) epidural or frontal lobe depth-electrode electroencephalography or (2) hippocampal c-fos-regulated gene expression. Heterozygous knock-in mice are partially protected from nicotine-induced seizures. The noncompetitive antagonist mecamylamine does not suppress the DAC, although it suppresses high-dose nicotine-induced wild-type-like seizures. Experiments on agonist-induced 86Rb+ and neurotransmitter efflux from synaptosomes and on alpha4S248Fbeta2 receptors expressed in oocytes confirm that the S248F mutation confers resistance to mecamylamine blockade. Genetic background, gender, and mutant gene expression levels modulate expression of the DAC phenotype in mice. The S248F mouse thus appears to provide a model for the paroxysmal dystonic element of ADNFLE semiology. Our model complements what is seen in other ADNFLE animal models. Together, these mice cover the spectrum of behavioral and electrographic events seen in the human condition.