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Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

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Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

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Nicotinic acetylcholine receptor mutations

, , and .

Author Information

,1 ,2 and 3.*

1 University Hospital, University of Munich, Munich, Germany
2 Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
3 Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan
*Corresponding author: Ortrud K. Steinlein, M.D., Ph.D., University Hospital, University of Munich, Goethestr. 29, 80336 München, Germany

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was the first idiopathic epilepsy in humans for which a causative gene defect could be identified. This rare genetic syndrome can be caused by mutations in at least two different subunits genes of the neuronal nicotinic acetylcholine receptor (nAChR), CHRNA4 and CHRNB2. First described in 1995, ADNFLE is characterized by clusters of brief motor seizures that occur mostly during non-REM sleep. It usually starts within the second decade of life but intra- as well as interfamilial variability of the phenotype is considerable. All but one of the known ADNFLE mutations were found either in the second or third transmembrane domain, which count only for a small part of the channel subunits but are functionally crucial for the ion pore. The clustering of the mutations and the repeated occurrence of some of these mutations in different countries suggest that within each subunit only a few amino acid residues are able to cause this type of epilepsy. In vitro expression studies showed that all mutations increase the receptors sensitivity towards acetylcholine, suggesting that a gain-of-function is the basic mechanism behind ADNFLE. However, the extent of the gain-of-function effect varies between mutations, and the mutated nAChRs display individual pathofunctional profiles for agonists such as nicotine or antiepileptic drugs like carbamazepine. It is therefore not surprising that the clinical phenotypes associated with the mutations are not uniform. ADNFLE mutations can be roughly divided into two types, one that in most patients causes only epilepsy and one that seems often to result in epilepsy accompanied by additional neurological features such as psychiatric symptoms, mental retardation or cognitive deficits.


Autosomal dominant frontal lobe epilepsy (ADNFLE) was described relatively recently as rare but a distinct familial idiopathic epilepsy in 1994 1. Contrary to this late nosological “discovery”, ADNFLE became the first idiopathic epilepsy which disclosed its underlying molecular pathogeneses, namely, nicotinic acetylcholine receptor (nAChR) mutations. As nAChR is a ligand gated ion channel, at the same time, this molecular discovery made ADNFLE the first epilepsy to be recognized as one of channelopathies or diseases resulting from channel dysfunction 2. The notion that epilepsy can be a channelopathy which was deduced from the molecular discovery on ADNFLE has certainly contributed to genetics of epilepsy 3. Supporting the notion, in fact, are some 20 other epilepsies which were recognized subsequently as “channelepsies”, that is compounders of channelopathy and epilepsy, indicating epilepsies resulting from channel dysfunctions 4. Such channelepsies include, among others, benign familial neonatal seizures (BFNS) resulting from mutations of potassium channels, genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome due to sodium channel mutations 3. Studies of ADNFLE in association with nAChR mutations have also established a methodology for investigating pathomechanisms of other epilepsies. Thus, dysfunction of ion channels due to genetic abnormalities can be evaluated readily in vitro, as ion channels can be reconstituted in oocytes or cultivated cells using relevant cDNA expression systems. These ion channel dysfunctions enable us to understand the molecular and neuroscientific pathomechanisms underlying epilepsies. Furthermore, this allows us to genetically engineer animal models of epilepsy, which harbour homologue mutations to those identified in human epilepsies 5–7. Such genetically engineered animal models of epilepsy represent molecular pathomechanisms distinct from those of conventional animal models. These genetically engineered animal models, which more accurately represent the pathomechanisms in the human brain, will open new avenues for treating epilepsies and developing novel measures for epilepsy based upon a better understanding of their molecular basis. In this chapter, we demonstrate the clinico-physiological characteristics of ADNFLE and summarize the current understanding of the molecular pathomechanisms of ADNFLE resulting from nAChR mutations.

Clinical spectrum of ADNFLE

ADNFLE is a literally partial epilepsy inherited as an autosomal dominant trait with penetrance as high as 90%. There is also sporadic nocturnal frontal lobe epilepsy (NFLE), which is non-familial. Its clinical manifestations are indistinguishable from those of ADNFLE 8–9. In fact, nAChR mutations may be found as a cause of sporadic NFLE 10. As their names suggest, predominant ADNFLE/NFLE seizures are symptomatically comparable to those of frontal lobe epilepsy whereas seizures occur exclusively, if at all, during non-rapid eye movement (NREM) sleep. Thus, ADNFLE/NFLE attacks occur during light sleep or even daytime and are characterized by clusters of brief seizures. These are often stereotyped and brief (5 seconds to 5 minutes), sometimes preceded by an aura including sensory or psychic symptoms. Such seizures may start with grunts, gasping or vocalization followed by hyperkinetic movements including dystonia and sleep-working. These brief seizures may sometimes evolve into secondary generalized tonic-clonic seizures. Retained awareness during seizures is common. To some degree, sleep disturbance may be associated with the seizures and hence affected individuals often complain of daytime fatigue after frequent seizure attacks during night. Although the seizure pattern of ADNFLE/NFLE per se is stereotypic, within a family, the manifestations may vary considerably ranging from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features.

Because of their mostly nocturnal occurrence, the attacks are often misdiagnosed as nightmares or parasomnias. Based on the observation of a large number of patients, Provini F. and colleagues have identified three distinct types of ADNFLE/NFLE seizure, “paroxysmal arousals,” “paroxysmal dystonia,” and “episodic wandering.” Paroxysmal arousal is characterized by brief and sudden recurrent motor paroxysmal behaviour. Paroxysmal dystonia is a motor attack with dystonic-dyskinetic features. Episodic wandering is stereotypical and agitated somnambulism 8. These cardinal manifestations may be a key to distinguishing nocturnal frontal lobe epilepsy from other parasomnias.

ADNFLE/NFLE onset ranges from infancy to adulthood. About 80% of patients develop ADNFLE/NFLE in their first two decades; mean age of onset is 14 years (14±10 years). The age of the onset, however, is known to vary among affected individuals, even those in the same pedigree. ADNFLE/NFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent. Still, like with seizure manifestations, there are intra and inter-familial variations in the natural course of ADNFLE/NFLE 9.

Apart from minor differences, the ADNFLE/NFLE clinical phenotype is mostly uniform. No proven relationship between phenotypes and genotypes of nAChR mutations (i.e., phenotype-genotype correlation) has been elucidated. To date, however, it has been reported that two clinical phenotypes may change according to genotypes of nAChR mutations. One such change is the intellectual impairment or cognitive deficit; the other is sensitivity to anti-epileptic drugs (AEDs) 8,11–12. While in most cases, neurological examinations are normal and there is no intellectual impairment, it is possible that the S284L mutation of CHRNA4 is associated with cognitive deficit 9–10,13 (details will be discussed in the following sections).

Genotypes of nicotinic acetylcholine receptor mutations may be associated with sensitivity to AEDs in ADNFLE/NFLE. Carbamazepine (CBZ), often in relatively low doses, provides remission to about 70% of individuals with ADNFLE/NFLE. CBZ, hence, remains the first-choice antiepileptic drug for treatment of ADNFLE/NFLE; however, resistance to AEDs, present in about 30% of affected individuals, requires a trial of other appropriate AEDs. Individuals with ADNFLE/NFLE associated with the CHRNA4-S284L mutation may respond only partially to CBZ but be more responsive to zonisamide (ZNS) or benzodiazepine 11–12,14.

EEG and brain imaging in ADNFLE patients

In recent years, studies with video-polysomnographic monitoring have identified a distinct form of clear-cut attacks originating from epileptic foci located in the frontal lobe and emerging almost exclusively during sleep (mainly NREM sleep II/III). During wakefulness, the electroencephalogram (EEG) of almost all patients with ADNFLE/NFLE (nocturnal frontal lobe epilepsy) is within the normal limits and the interictal EEG during sleep is also normal 8,15. A few ictal EEG recordings display a clear-cut epileptic activity (spikes and spikes & waves), and in a few subjects, diffuse (background flattening) or focal EEG activity may be recorded (rhythmic theta or delta activity prominent over the anterior quadrants) 8,15–16. The interictal EEGs showed no abnormality in more than 50 % of patients with ADNFLE 17. Therefore, without simultaneous video and polygraphic recordings of seizures, the lack of EEG epileptic abnormalities does not exclude ADNFLE/NFLE. Ictal EEGs show that seizure activity is of frontal origin, and occurs predominantly in stage 2 NREM sleep 11 (Figure 1). The failure to disclose abnormalities in many patients may be due to the inaccessibility of the locus to scalp EEG recordings 11,17. Subdural grid recordings, sphenoidal or zygogomatic recordings, PET, and SPECT also confirmed the frontal origin of seizures in patients with ADNFLE 11,18–20. As for the relation between arousal and seizures, seizure onset usually preceded arousal in patients with ADNFLE. Seizure onsets often coincided with the recording of K-complexes in the EEG and were some times triggered by sound stimuli 21. In Japanese ADNFLE patients, the seizures were not always associated with arousal from sleep, but long seizures sometimes produced arousal 11. A careful medical and family history of nocturnal symptoms, video-EEG monitoring of seizures and gene analysis are enormously helpful for making an accurate diagnosis of ADNFLE.

Figure 1. Ictal EEG of an Japanese ADNFLE patient with mutation CHRNA4-S284L.

Figure 1

Ictal EEG of an Japanese ADNFLE patient with mutation CHRNA4-S284L. Low-voltage spikes were initiated from the frontal region, gradually increased in amplitude, and were followed by high-voltage slow waves (modified from ).

A case: This boy’s birth was via uncomplicated vaginal delivery after a normal pregnancy. At age 7 months, he had an afebrile general tonic convulsion during the daytime. The duration was 10 min. Interictal EEG showed no abnormality. He was diagnosed as having infantile convulsions and therefore was not treated with AEDs. At age 11 months, he began to have nocturnal seizures. His mother considered these to be "nightmares," At age 1 year and 3 months, he was admitted to a hospital for further evaluation. He had five to six seizures during stage 2 of NREM sleep at night and during midday naps. His seizures were sometimes provoked by movement and sound stimulation. The duration of each seizure was 10–15 s. During overnight video-EEG monitoring, five seizures were detected, and one of the seizures was provoked by movement. All the seizures were identical in their clinical and electrographic manifestations. MRI showed no abnormality, but SPECT detected low perfusion in both frontal lobes. Interictal EEG showed rare sporadic single spikes over the left Fp. lctal EEG showed low-voltage spikes initiating from the frontal region that gradually increased in amplitude and were followed by high-voltage slow waves (Figure 1). He was treated with CBZ and cloxazolam. However, seizure control was not achieved (Ito 2000).

ADNFLE mutations in nicotinic acetylcholine receptor subunits

ADNFLE, although classified as a partial epilepsy, turned out to be caused by mutations in genes that are ubiquitously expressed in brain. The first ADNFLE mutation had been found in 1995 in a large Australian family 2. All affected family members available for mutation analysis carried a S280F amino acid exchange within the second transmembrane domain of CHRNA4. The same amino acid exchange was later found again in families from Spain, Norway and Scotland 22–25, and additional ADNFLE mutations were identified within CHRNA4 but also in the homologous gene CHRNB2 10,23,26–32. All mutations identified so far are heterozygous. All but one of these mutations are amino acid exchanges that affect highly conserved residues. An exception is CHRNA4-865-873insGCT (also named 773ins3 27), a three base pair insertion that adds a fourth leucine residue to a sequence stretch that already contains three consecutive leucines. The ADNFLE mutations cluster either in the second TM (CHRNA4) or in both the second and the third TM (CHRNB2). Mutations in the second TM, the major pore-forming part of each nAChR subunit, mostly affect amino acids that are part of the amino acid residue axis that rotates when agonists such as acetylcholine attach to the binding site, opening the ion channel. These mutations are therefore likely to interfere with the channel’s kinetics. The pathomechanisms behind mutations in the third TM are less well understood. It seems plausible that these mutated amino acids are in direct or indirect contact with residues in the second TM, because mutations in the third TM are also able to change the channel’s opening and closing kinetics 31. Only one recently in a single Chinese patient described mutation, CHRNA4-R336H (also named R308H 29), locates downstream of TM2-3 in the second intracellular loop, a structure of unknown significance for receptor function 29. This mutation hasn’t been functionally characterized yet and not enough clinical details are given in the original paper to allow a comparison with known ADNFLE phenotypes. A putative third ADNFLE gene is CHRNA2, a nAChR subunit gene that has been found mutated in a single Italian family with sleep-related epilepsy 34. CHRNA2 is one of the major nAChR subunit genes and almost as ubiquitously expressed in brain as CHRNA4 and CHRNB2. It nevertheless seems to be a much rarer case of epilepsy than the latter two genes, as no additional mutations have been reported yet 35. Overall mutations of CHRNA4, CHRNB2 or CHRNA2 are found in less than 20% of individuals with the ADNFLE/NFLE phenotypes 36, suggesting genetic heterogeneity of ADNFLE/NFLE.

Neuronal nicotinic acetylcholine receptors

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand gated cationic channels that are composed of various combinations of five subunits arranged quasi-symmetrically around a central channel. They are encoded by nine α (α2-α10) and three β (β2-β4) subunit genes that show distinct patterns of expression both in neuronal and non-neuronal tissues. Each subunit is composed of three different parts, which include the extracellular, cytoplasmatic and transmembrane portions. The NH2-terminus is the largest extracellular domain, contains several glycosylation sites and, in α subunits, contributes the main components of the high-affinity ligand binding sites that are located at the interface between neighbouring subunits. This domain is important for receptor assembly and expresses the main immunogenic region. The four transmembrane regions (TM) probably have a mixed α-helical/non-helical secondary structure with their helical segments forming both an inner ring (TM2) that shapes the pore and an outer shell (TM3-TM4) that shields the inner ring from membrane lipids. The different subunits assemble to build two classes of nAChRs, the homomeric or heteromeric α-Bungarotoxin-sensitive receptors that are composed solely from α subunits (α7-α10), and the heteromeric α-Bungarotoxin-insensitive receptors that consist of various combinations of α and β subunits (α2-α5, β2-β4). The mechanisms of nAChR activation, ion pore opening and closure and desensitisation are determined by highly conserved amino acid positions within the subunits. The function of the different neuronal nAChR subtypes depends on their subunit composition, their distribution within the brain as well as on their cellular location. Postsynaptic nAChRs often contribute to fast excitatory transmission, while preterminal and presynaptic nAChRs enhance neurotransmitter release (which, depending on the released transmitter, either increases inhibitory or exitcatory synaptic impulses), and nonsynaptic nAChRs are likely to modulate neuronal excitability 37. The nAChRs are involved in brain development and plasticity and participate in many different brain functions, including modulation of sensory inputs, locomotor activity, analgesia, attention, learning, memory and reward mechanisms. It is therefore not surprising that genetic variants in nAChR subunit genes were found to be associated with different common disorders and behaviours, including Alzheimer disease, schizophrenia and smoking related endophenotypes 38–44. However, the only monogenic disorder so far known to be caused by high penetrance mutations in neuronal nAChR is ADNFLE.

In vitro expression of ADNFLE mutations

The exact nAChR subtype compositions in different brain regions are not fully understood. This is due to the fact that various ligands are not sub-type specific and highly specific antibodies are not available for all subunits yet. Probes for in situ hybridization on nAChR mRNAs are also not specific enough which inevitably led to false positive results 45–46. The expression patterns for specific subunits may differ among species. Some nAChR subtypes such as α2β3 and α4α6β2β3 receptor subtypes are expressed in restricted region of the brain and may have specific roles in brain function, while such subtypes as the α4β2 nAChR are expressed ubiquitously and highly bind most nicotinic agonists 47–50. To study functional changes of mutated AChRs, whole-cell patch-clamp is often applied. Controversial data have been reported from in vitro expression studies, i.e. loss of function and gain of function of receptors with CHRNA4 mutations. Some reports indicated the acceleration of desensitization of receptors which leads to lowered Ca2+ permeability 2,22–23,27,51 while increased affinity of receptors to ACh which leads to gain of function has also been reported 10. Retardation of desensitization (V287L) or increased affinity to AChRs (V287M) has been reported for CHRNB2 mutations 52–53. In vitro expression studies showed that all mutations increase the receptors sensitivity towards acetylcholine, suggesting that a gain-of-function may be the basic mechanism behind ADNFLE 28,34,53–55. However, the extent of the gain-of-function effect varies between mutations, and the mutated nAChRs display individual pathofunctional profiles for agonists such as nicotine or antiepileptic drugs like CBZ and ZNS. Most ADNFLE patients respond to CBZ while patients with specific mutations such as CHRNA4-S284L are more likely to respond to ZNS 11. A reduction of the Ca2+ dependence may also be a common mechanism 56. The functional involvement of the GABAergic system in the pathophysiology of ADNFLE deduced from model animals will be discussed separately 5,7.

A recent study found that individuals with micro deletions of chromosome affecting both KCNQ2 and CHRNA4 presented with only the BFNS phenotype and lacked ADNFLE/NFE semiology 57. This finding along with the fact that all nAChR mutations identified in ADNFLE were heterozygous, suggests that the autosomal dominant inheritance mode of ADNFLE is attributable to the dominant negative or dominant positive effect, in accordance with the “gain-of-function” of mutant receptors. It is plausible that mutant subunits exert their effects as components of multimeric nAChR.

Origin of seizures

ADNFLE mutations in the nAChR subunits appear to modify the number and distribution of α4β2 nicotinic receptors in the living human brain. The distribution of α4β2 nicotinic receptors has been studied in eight ADNFLE patients carrying nicotinic receptor mutations (causative mutations: four patients with α4-S280F (numbering according to reference sequence NP_000739.1) (mutation is also named S248F 2); two with α4-S284L (also named S252L 26); one with α4- T293I (also named T265I 28); and two with β2-V287L), by a PET-scan using [18F]-F-A-85380, a radioligand with a high affinity for α4β2 nAChRs. This PET study demonstrated a regional nAChR density decrease in the prefrontal cortex, an observation consistent with partial epilepsy involving the frontal lobe. The increase of nAChR density in the mesencephalon suggests that these brain structures are involved in the pathophysiology of ADNFLE through the role of brainstem ascending cholinergic systems in arousal 33. Electrophysiological studies of the receptors carrying the different mutations identified a common alteration in their properties, corresponding to a gain of function. However the precise mechanisms leading to the frontal lobe epilepsy remain elusive.

Genotype – phenotype correlations in ADNFLE

The results of a pilot study in which 11 ADNFLE patients with different mutations were assessed by neuropsychological evaluation suggested that mild cognitive problems might be a common minor feature of the disorder 33. However, even ADNFLE mutations that affect neighbouring amino acid residues seem to differ significantly with respect to their major clinical features. Mutations such as CHRNA4-S280F and CHRNB2-V287M or V287L are usually associated with epilepsy as the sole major symptom and additional neurological features have been reported in just about 2% of patients with these mutations. This is especially obvious for CHRNA4-S280F where in 65 out of 67 known patients that belong to a total of five families with this mutation the only reported major symptom is epilepsy 2,22–23,25. In patients with mutations such as CHRNA4-S284L, CHRNA4-865-873insGCT (also named 776ins3 27) or CHRNB2-I312M additional major neurological features are reported in an average of 70% of patients. Comparison of unrelated families with the same ADNFLE mutation suggests that these additional major neurological features tend to be specific with each mutation. The mutation CHRNA4-S284L has been described in families from Japan, Korea and Lebanon, and at least 11 of the 16 patients from these families are of borderline intelligence or mildly retarded 10,13,26. Selective cognitive deficits that mostly affect verbal memory seem to be typical for mutation CHRNB2-I312M and have been described in all of the four known patients from two families of different ethnic background 13,32. Patients with CHRNA4-865-873insGCT show a high comorbidity for psychiatric disorders such as the negative symptoms of schizophrenia 24. The ethnic differences between families with the same mutation and the cosegregation of epilepsy and additional neurological features in multiplex pedigrees strongly suggest that the observed genotype-phenotype correlations are not coincidental, although so far not enough families with these mutations are known to confirm this hypothesis. At a first glance it seems difficult to explain how mutations that affect amino acid residues located within the same functional domain, often only a few residues apart, could differ this drastically in their associated clinical features. It has been speculated that allosteric coupling between amino acids links functional elements within the nAChR that are far apart in the primary amino acid sequence 59. Following this theory adjacent amino acids might differ with respect to the functional elements they interact with in other parts of the subunit. That would explain why functional studies showed that ADNFLE mutations tend to differ from each other with respect to their biopharmacological profiles 31. The nAChRs are involved in many important brain functions and even such subtle functional differences are therefore likely to have an impact on the clinical phenotype.

Animal models of ADNFLE – what did we learn?

Several genetic animal models bearing mutant genes that have been identified in families with idiopathic epilepsy have been generated. However, to explore the pathogenesis of ADNFLE, it is important that the genetic epilepsy animal models fulfil the validation criteria for such models (face validity, construct validity, and predictive validity). 60–61. Face validity is the ability to fundamentally mimic the behavioural clinical characteristics of the disorder. Construct validity conforms to a theoretical rationale for the disorder. Predictive validity is the ability to predict previously unknown aspects of behaviour, genetics, and neurobiology of the disorder from the model.

1. Specific criteria for genetic animal models of ADNFLE

In general, the optimal animal model should mimic the human disorder in terms of etiology, biochemistry, symptomatology, and treatment 62. The ADNFLE model should exhibit spontaneous epileptic seizures resembling paroxysmal arousals, nocturnal paroxysmal dystonia and episodic nocturnal wandering, during NREM sleep. The interictal EEG may or may not be normal. The foci of ictal or interictal discharges should be localized in frontal or over the anterior quadrants. The age of onset of AFNFLE would ideally be around puberty. CBZ might reduce both the frequency and complexity of seizures in model animals as it does in more than 60% of patients with ADNFLE/NFLE, including those with CHRNA4-S280F and CHRNA4-865-873insGCT mutations 14–15,63. However, CBZ efficacy is not obligate in animal models as some patients (individuals with CHRNA4-S284L 10–11,64, CHRNA4-T293I 28, CHRNAB2V287M 53, and CHRNAB2-I312M 32 are resistant to CBZ but susceptible to other antiepileptic drugs, such as acetazolamide, benzodiazepine (BZP), topiramate and zonisamide (ZNS) or antiepileptic drugs-resistant 10–11,13–15,53,65. Among ADNFLE patients with CHRNA4-S284L-mutation autism and mental retardation have been reported 11,58, and ADNFLE patients with the CHRNA4-865-873insGCT mutation showed schizophrenia-like psychosis 24. Therefore behavioural studies should be part of the study design for animal models of ADNFLE. The knock-in technique is probably appropriate to create genetic animal models of ADNFLE; however, the expression pattern and expression levels of the trans-gene in the genetic animal model must be confirmed because in some knock-in techniques promoters are used that are not naturally occurring in rodents.

2. Validities of genetic animal models of ADNFLE

The validities of four genetic animal models of ADNFLE are summarized in Table 1 66. The phenotypes of the two strains of knock-in mice with the CHRNA4-S280F mutation are different, since one strain exhibits spontaneous epileptic seizures (pS280F-KM), while the other does not (nS280F-KM) 5–6. The spontaneous epileptic seizures of pS280F-KM are observed in wakefulness but not during sleep 5. The seizures are characterized by paroxysmal onset and sudden termination. The ictal discharge of pS280F-KM shows complex patterns of spike and wave activity with a high-amplitude and low-frequency power spectrum, the background activities in the EEG of the pS284F-KM animal model show abnormal patterns characterized by marked increase in δ-wave activity (0.5–4 Hz) 5. Contrary to pS284F-KM, no abnormalities are detected in the background EEG activities of nS284F-KM rat 6. The knock-in mouse with CHRNA4-865-873insGCT (insL-KM) exhibits epileptic wandering-like spontaneous epileptic discharges with paroxysmal onset and sudden termination during wakefulness 5. The EEG features of the insL-KM mice are similar to pS284F-KM. The ictal discharges of insL-KM show complex patterns of spike and wave activity with high-amplitude and low-frequency power spectrum. The EEG of insL-KM during spontaneous seizures shows a more asymmetric and diffuse pattern than that of pS284F-KM. The EEG background activities of insL-KM show also marked increase in δ-wave activity 5.

Table 1. Validity of ADNFLE models.

Table 1

Validity of ADNFLE models.

The transgenic rat carrying the CHRNA4-S284L mutation (S284L-TG) exhibits the three distinct ADNFLE seizure characteristics during NREM sleep; paroxysmal arousals (brief episodes characterized by sudden frightened expression), paroxysmal dystonia (brief episodes of dystonic posturing), and epileptic wandering (episodes of longer duration ranging from 1 to 3 min with head shaking accompanied by stereotyped paroxysmal ambulation and bizarre movements) 67. The onset of ictal discharges is synchronized with seizure behaviours. No abnormalities of background activities are observed in the EEG of the S284L-TG rat. The focus of both ictal and interictal discharges is the frontal sensorimotor cortex region. Usually the onset of interictal discharges starts after 6 weeks of age; however, the onset of spontaneous ADNFLE seizures is preceded by that of interictal discharges in the same transgenic rat. At 8 weeks of age, 90% of S284L-TG rats exhibit spontaneous seizures during NREM sleep. The characteristics of epileptic seizures of S284L transgenic rats are quite similar to those of ADNFLE patients with the same mutation 67. The published phenotypic features of the above described four genetic animal models of ADNFLE show that the face validity of the S248L-TG rat is adequate, whereas neither the pS280F-KM, nS280F-KM nor insL-KM mice are suitable genetic animal models to study the clinical phenotype of ADNFLE. Both knock-in mice, pS280F-KM and insL-KM, are considerably more sensitive to nicotine-induced seizures than wild-type mice. Indeed, in nicotine-induced seizure tests, these two types of knock-in mice show a lower threshold dose of nicotine for generalized seizures with shorter latencies to seizure onset, and exhibit longer seizure durations compared with their wild-type littermates 5. Knock-in mice with CHRNA4-S280F (nS280F-KM) which do not exhibit spontaneous epileptic seizures, did not display a particularly different response in nicotine-induced seizure tests, compared with wild-type mice. However, they developed ADNFLE-like epileptic wandering following administration of 1 mg/kg nicotine, and these seizures were prevented by supratherapeutic doses of CBZ 6. No difference was observed between S284L-TG and non-TG littermates in the latency of nicotine-induced seizures. Nicotine-induced seizures in S284L-TG transgenic rats were mainly partial seizures, whereas those in non-TG littermates were generalized seizures. In S284L-TG, sub-chronic administration (two weeks) of diazepam and zonisamide at therapeutically relevant doses reduced the frequency of interictal discharges by 43 and 48%, respectively, whereas at therapeutically-relevant doses, CBZ had no effect on the frequency of interictal discharge 67.

The results of the nicotine-induced seizure test showed different responses among the four genetic animal models of ADNFLE. However, the nS280F-KM and S284L-TG developed ADNFLE-like seizures, epileptic wandering (nS280F-KM and S284L-TG), paroxysmal arousal (S284L-TG) and paroxysmal dystonia (S284L-TG) in response to nicotine administration. Thus, the predictive validity of S284L-TG as a model for pharmacological effects in ADNFLE has been demonstrated, whereas neither that of nS280F-KM, pS252F-KM nor insL-KM has been established.

The trans-gene promoter of S284L-TG is not a naturally occurring rodent promoter but a mammalian PDGF-β promoter that activates preferentially in certain brain tissues 6–7. In situ hybridization using a nonselective probe (sensitive to both wild-type and S284L mutant Chrna4 mRNA) showed no differences in the cerebral expression of Chrna4 mRNA between non-TG and S284L-TG. The total amount of Chrna4 mRNA (wild-type plus S284L Chrna4) in the frontal cortex of S284L-TG was almost equal to that in non-TG. The expression of wild-type versus S284L Chrna4 was 45% versus 55%. In the focus region, there was no significant difference in the number of nAChR α4-immunopositive neurons between non-TG and S254L-TG. No distorted expression of wild-type or S284L Chrna4 was observed in the cell populations of neurons, astrocytes and oligodendrocytes. In spite of these, the wild-type Chrna4 mRNA is predominantly expressed in the thalamus and cortex, whereas the S284L mutant Chrna4 mRNA is mainly expressed in the cortex and thalamus. Laser-capture microdissection with single-cell reverse-transcription quantitative PCR has demonstrated the lack of ectopic expression of the transgene in neurons and glial cells.

The question remains why the pS280F-KM but not the nS280F-KM exhibit spontaneous epileptic seizures. There is little or no information on the expression of mutant Chrna4 gene or nAChR α4-subunit protein in the pS280F-KM, nS280F-KM and insL-KM animals 5–6. Although the promoter in these knock-in techniques is a natural promoter, the mRNA and protein expression levels of S280F mutant Chrna4 still need to be determined. At present, there are not any suitable ADNFLE genetic animal models according to the construct validity. To study the pathogenesis and pathophysiology of ADNFLE, knock-in mice with established construct validity or transgenic animal models with a natural promoter should be generated 66.

3. Pathophysiology of ADNFLE

In spite of these limitations with ADNFLE model animals, it is interesting to note that S284L-TG rats showed 1 attenuation of synaptic and extrasynaptic GABAergic transmission and 2 abnormal glutamate release during slow wave sleep. In mice bearing two engineered chrna4 (S252F or +L263) mutations, the involvement of inhibitory synchronization of cortical networks via activation of mutant alpha4-containing nAChR located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons has been suggested 5. Further analysis of the molecular biology of these abnormal neurotransmissions will help to uncover some of the mechanisms underlying ADNFLE, improving our understanding of the pathogenesis, epileptogenesis and ictogenesis and ultimately lead to the development of new treatments.

Key question: Why do nAChR mutations cause epilepsy?

Most seizures are characterized by short bursts of abnormal neuronal activity that, by their origin and spreading pattern in brain, determine the clinical phenotype of the epilepsy. Seizures often arise from a state of hypersynchronisation that causes groups of neurons or whole neuronal networks to fire simultaneously. In ADNFLE these episodes are usually occur with NREM sleep phases 63 that can be subdivided into two main phases, one that consists of transient arousals and one that is characterised by tonic activities in the EEG. The association between the seizures and NREM phases suggests that sleep-controlling brain structures are involved in the pathogenesis of ADNFLE. One of the main regulators of sleep is the central cholinergic system that controls both the circadian clock and the sleep-wake cycle. An important component of it are cholinergic neurons within the central reticular core of the brain, where the basic sleep-waking cycle is determined. From there two major cholinergic cell groups are responsible for the cerebral activation that accompanies wakefulness and paradoxical sleep. One is located within the pontomesencephalic tegmentum that projects rostrally into the non-specific thalamo-cortical relay system and the other is placed within the basal forebrain that receives input from the brainstem reticular formation and projects as the ventral, extrathalamic relay upon the cerebral cortex 67–68. Functional changes in nAChRs as those induced by ADNFLE mutations might affect these cholinergic projections and cause aberrations in sleep stages that, for unknown reasons, render certain neuronal networks more vulnerable for sudden bursts of hyperactivity during NREM sleep. Such bursts of hyperactivity could have their origin in the gain-of-function effect caused by ADNFLE mutations in nAChRs located on GABAergic interneurons. At least two mechanisms are discussed that are both able to explain how changes in GABAergic interneuron activity might play a central role in seizure generation. The older hypothesis postulates that seizures are the result of reduced inhibition that causes an increase in excitatory neuronal activity. More recently it has been shown that the opposite mechanism is at least as plausible, and is the one most likely involved in seizures caused by nAChR subunits. The basic principle underlying this mechanism is an enhancement of neuronal synchrony by inhibition. It has been shown that pyramidal cells that are connected to the same GABAergic interneuron synchronise their firing when released from the interneuron’s inhibitory effect 69. Interneurons innervating layer II/III pyramidal cells are known to carry α4β2 nAChRs. Triggered by the gain-of-function effect ADNFLE mutations exhibit on these receptors they could activate larger numbers of GABAergic interneurons that in turn could easily synchronise enough pyramidal cells to change local cortical activity from synchronisation to hypersynchronisation. Spreading of the hypersynchronisation into the motor control area would than be likely to cause the type of seizures typically associated with ADNFLE. Such a mechanism in which a gain-of-function of certain nAChR subunits causes hypersynchronisation by increasing GABAergic inhibition is supported by some of the above described animal models. GABA antagonists such as picrotoxin have shown to normalize the EEG and suppress spontaneous seizures in genetically altered pS280F-KM mice 5. Nevertheless, many details of epileptogenesis in ADNFLE remain unknown and are subject for further studies.


nAChR mutations identified in ADNFLE/NFLE have facilitated our understanding of the pathogeneses not only of these unique and relatively rare epilepsies but also of other epilepsies. Our understanding should open new avenues to developing novel measures against epilepsy based upon molecular pathomechanisms. Consecutive studies of ADNFLE/FLE in association with nAChR mutations have for the first time provided compelling evidence that genetic predispositions closely associate with the pathogeneses of epilepsy on the molecular level. Thanks to the breakthrough in ADNFLE/NFLE research, novel methodologies have been established in epileptology. They range from evaluations of channel mutations in vitro to genetically engineered animals models bearing the mutations identified in human epilepsy. Continuing studies utilizing such methodologies should delineate all the pathomechanisms of single mutations or genetic predispositions that result in epilepsy. These could not have been learnt only through clinico-electrophysiological studies. Once the molecular pathomechanisms of epilepsy are revealed, it should be possible to cure epilepsy completely by blocking part of the pathomechanisms. Since the discovery of nAChR mutations in ADNFLE/NFLE, we have now reached the position where novel therapies based upon the molecular pathomechanisms of epilepsy can be designed. Such therapies will bring relief to individuals suffering from epilepsy and the adverse effects of conventional AEDs.


This work was supported by the DFG (STE16511-2) to OKS. The work of SK was supported by a Grant for Hirosaki University Institutional Research, a Grant from Hirosaki Research Institute for Neurosciences, a Grant In -Aid for Scientific Research (S) 12109006, (A) 12307019, and Grants from the Ministry of Health and Labor Science research. The work of SH was supported in part by Grant-in-Aid for Scientific Research (S) 16109006, (A) 18209035 and (A) 21249062, Exploratory Research 1659272, and by a “High-Tech Research Center” Project for Private Universities: matching fund subsidy from the Ministry of Education, Culture, Sports, Science and Technology, “The Research Center for the Molecular Pathomechanisms of Epilepsy, Fukuoka University”. Additional funds to SH were provided by Research Grants for Nervous and Mental Disorder (19A-6 and 21B-5), and Health and Labor Science Research Grant 21210301 from the Ministry of Health, Labor and Welfare, and the Central Research Institute of Fukuoka University to SH.


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Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

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