Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology

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.

The β2V287L nicotinic subunit linked to sleep-related epilepsy differently affects fast-spiking and regular spiking somatostatin-expressing neurons in murine prefrontal cortex

“…Finally, our observations may also explain why nicotine is effective as an anti-seizure treatment, in a fraction of ADSHE patients carrying nAChR variants (Becchetti et al, 2020;Fox et al, 2021). Administration of the drug throughout the day could increase the efficacy of surround inhibition in frontal regions, during brain stages characterized by low ACh release.…”

“…when the cholinergic tone is lowest (Jones, 2020). Our study is also relevant to understand why nicotine treatment controls seizures in a fraction of human ADSHE patients (Becchetti et al, 2020).…”

“…First, using ACh requires adding muscarinic antagonists, whose effects on nAChR subtypes are ill-defined (e.g., Zwart and Vijverberg, 1997). Second, nicotine has been used to control the symptoms in ADSHE patients (Becchetti et al, 2020). Nicotine was applied in the bath at 10 µM, which corresponds to the peak of nAChR 'window current', thus producing maximal steady state activation of heteromeric nAChRs (Fenster et al, 1997).…”

Association Study of Polymorphisms in Neuronal Nicotinic Acetylcholine Receptor Subunit Genes With Schizophrenia in the Han Chinese Population

“…CHRNA4 is located on chromosome 20 at position 20q13.2-q13.3. Some SNPs of CHRNA4 were found to be associated with many psychiatric disorders, such as schizophrenia, Alzheimer’s disease (AD), attention-deficit/hyperactivity disorder (ADHD), Parkinson’s disease (PD), and nicotine dependence [ 29 , 30 ]. More specifically, a single nucleotide polymorphism in the CHRNA4 gene (rs1044396) appears to affect visual and auditory function, affecting speed and attention [ 31 ].…”

Fluorescently Labeled α-Conotoxin TxID, a New Probe for α3β4 Neuronal Nicotinic Acetylcholine Receptors

“…It is worth noting that the nAChR subtypes have different pharmacological sensitivities, due to different subunits, but their structures are very similar and difficult to distinguish [ 7 , 8 ]. Neuronal-nAChR subtypes are involved in a range of disease states, including Parkinson’s disease, Alzheimer’s disease, sleep-related hypermotor epilepsy, nicotine addiction, and lung cancer [ 9 , 10 , 11 , 12 , 13 ].…”