The role of the nicotinic acetylcholine receptors in sleep-related epilepsy
Introduction
Whilst the idiopathic generalized epilepsies have always been regarded as genetic in origin, focal epilepsies have generally been considered as acquired. However, recent findings demonstrate that some focal epilepsies have a predominant genetic component and specific gene mutations have been identified in a few syndromes of focal epilepsy [1], [2], [3], [4]. These mendelian epilepsies are mainly associated with mutations in the genes coding for subunits of voltage-gated and ligand-gated ion channels [5]. In particular, mutations in genes coding for subunits of the ligand-gated nAChRs, associated with a form of inherited nocturnal frontal lobe epilepsy (ADNFLE), have clearly established a causative relationship between nAChRs dysfunction and epilepsy.
Section snippets
The phenotype
ADNFLE is a peculiar form of focal epilepsy with about 70% penetrance [6]. More than a hundred families have been reported to date [7]. Seizures typically start in middle childhood, usually between 8 and 11.5 years, but can begin anytime from infancy to the sixth decade, with clusters of attacks arising from sleep [6], [7]. Each cluster features a mean of six attacks but patients with up to 70 seizures per cluster have been described [6]. Seizures usually occur very soon after falling asleep or
ADNFLE: molecular genetic
ADNFLE was the first human idiopathic focal epilepsy for which specific gene mutations were described [3]. In 1995, a large Australian family was linked to chromosome 20q and a genetic defect was identified in the α4 subunit of the neuronal acetylcholine receptor gene (CHRNA4) [3] (Table 1). The causative role of CHRNA4 in ADNFLE was further supported by the observation of mutations in a few other families (Table 1) [22], [23], [24], [25], [26], [27], [28], [29], [30]. Few years later,
The neuronal nicotinic acetylcholine receptors (nAChRs)
Most of the current knowledge about the structure and function of nAChRs comes from studies in rodents and chicks, and information concerning human nicotinic receptors is still incomplete. Nevertheless, it is known that the nAChRs are membrane proteins with four transmembrane domains, and comprise an assembly of five subunits. So far, 12 nAChRs subunits have been identified (α2–α10 and β2–β4) [38]. Based on subunits composition, there are several different nAChRs, all of which have their own
How mutations in nAChRs can cause ADNFLE?
Molecular genetic studies have clearly shown the determinant role of nAChRs in ADNFLE. The first step toward understanding the basic mechanisms underlying epileptogenesis in ADNFLE is to examine the functional properties of mutated nAChRs.
Therapeutic implications of nAChRs in epilepsy
Some pieces are still missing in the puzzle of how nAChRs dysfuntion causes the ADNFLE phenotype and new therapeutic strategies arising from such knowledge are very far behind.
Carbamazepine (CBZ) is certainly the most effective antiepileptic drug in some ADNFLE patients, and an increased sensitivity of mutant nAChRs to CBZ might be the hypothetical underlying mechanism [57]. CBZ-binding through an inhibition of the hyperfunctional mutated nAChRs may lead to a reduction in seizure frequency in
Conclusions
The mutations identified in the CHRNA4, CHRNB2 and CHRNA2 genes in ADNFLE families strongly establish to role of the cholinergic system in this inherited epilepsy. Functional characterization of known mutations suggests that increased gain of the receptor function is at the origin of seizures. In vitro and in vivo studies have demonstrated a high density of nAChRs in the thalamus [32], [56] and an over activated cholinergic pathway, reinforcing the hypothesis that cortico-subcortical networks,
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