Abstract
Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic focal seizures, mainly arising in the neocortex during non-rapid eye movements (NREM) sleep. The familial form is autosomal dominant SHE (ADSHE), which can be caused by mutations in genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR), Na+-gated K+ channels, as well as non-channel signaling proteins, such as components of the gap activity toward rags 1 (GATOR1) macromolecular complex. The causative genes may have different roles in developing and mature brains. Under this respect, nicotinic receptors are paradigmatic, as different pathophysiological roles are exerted by distinct nAChR subunits in adult and developing brains. The widest evidence concerns α4 and β2 subunits. These participate in heteromeric nAChRs that are major modulators of excitability in mature neocortical circuits as well as regulate postnatal synaptogenesis. However, growing evidence implicates mutant α2 subunits in ADSHE, which poses interpretive difficulties as very little is known about the function of α2-containing (α2*) nAChRs in the human brain. Planning rational therapy must consider that pharmacological treatment could have different effects on synaptic maturation and adult excitability. We discuss recent attempts towards precision medicine in the mature brain and possible approaches to target developmental stages. These issues have general relevance in epilepsy treatment, as the pathogenesis of genetic epilepsies is increasingly recognized to involve developmental alterations.
Highlights
Epilepsy is a common neurological disease, whose hallmark is the presence of recurring “seizures”, i.e., transient events of abnormal neuronal activity in the brain that cause recognizable signs [1].Overall, life expectancy is lower in epileptic patients, and the incidence of sudden death higher, not to speak of the deteriorated quality of life and social stigma [2]
This is a further indication that a functional distinction can be traced between α2 and other nicotinic acetylcholine receptor (nAChR) subunits, whose loci are linked to the latter psychiatric disorders [90] and whose expression is altered in patients thereof [91,92]
The possibility of carrying out sophisticated kinetic analyses of the effects of drugs targeting ion channels could lead to precision medicine aimed at modulating specific channel types and possibly individual mutations
Summary
Epilepsy is a common neurological disease, whose hallmark is the presence of recurring “seizures”, i.e., transient events of abnormal neuronal activity in the brain that cause recognizable signs [1]. The main nAChR subtypes in the brain are the homopentamer (α7) and the heteropentamer α4β2* The former presents lower affinity for ACh, with half-effective concentration (EC50 ) of ~100–200 μM, quick desensitization (time constant in the order of milliseconds), and a permeability ratio between. ACh release events evoked by sensory cues or optogenetic stimulus present a rise time of 0.2–0.5 s and peak levels of approximately 4–6 s [44] Such a time scale covers the time constant of desensitization of different heteromeric nAChR subtypes, justifying the conclusion that the alterations of current kinetics and sensitivity to the agonists observed in ADSHE-linked nAChR variants (discussed later) is a relevant factor in causing pathophysiological effects in neocortex networks
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