Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

Abstract

Kedmi, Merav, Arthur L. Beaudet, and Avi Orr-Urtreger. Mice lacking neuronal nicotinic acetylcholine receptor ␤4-subunit and mice lacking both ␣5-and ␤4-subunits are highly resistant to nicotineinduced seizures. Physiol Genomics 17: 221-229, 2004. First published March 2, 2004 10.1152/physiolgenomics.00202.2003.-Nicotine, the main addictive component of tobacco, evokes a wide range of dose-dependent behaviors in rodents, and when administrated in high doses, it can induce clonic-tonic seizures. Nicotine acts through the nicotinic acetylcholine receptors (nAChRs). Mutations in the human ␣4-and the ␤2-nAChR subunit genes cause autosomal dominant nocturnal frontal lobe epilepsy. Using transgenic mice with mutations in nAChR subunits, it was demonstrated previously that the ␣4-, ␣5-, and ␣7-subunits are involved in nicotine-induced seizures. To examine the possibility that the ␤4-subunit is also involved in this phenotype, we tested mice with homozygous ␤4-subunit deficiency. The ␤4 null mice were remarkably resistant to nicotine-induced seizures compared with wild-type and ␣5 null mice. We also generated mice with double deficiency of both ␣5-and ␤4-nAChR subunits and demonstrated that they were more resistant to nicotine's convulsant effect than either the ␣5 or the ␤4 single mutant mice. In addition, the single ␣5 mutants and the double ␣5␤4-deficient mice exhibited a significantly shorter latency time to seizure than that of the wild-type mice. Our results thus show that ␤4-containing nAChRs have a crucial role in the pathogenesis of nicotine-induced seizures. Furthermore, by comparing multiple mutant mice with single and double subunit deficiency, we suggest that nicotinic receptors containing either ␣5-or ␤4-subunits are involved in nicotine-induced seizures and that receptors containing both subunits are likely to contribute to this phenomena as well. However, the ␣5-subunit, but not the ␤4-subunit, regulates the rate of response to high doses of nicotine.neuronal nicotinic acetylcholine receptor ␣5-and ␤4-subunits; knockout mice NICOTINE ACTS THROUGH THE nicotinic acetylcholine receptors (nAChRs) and can be toxic in high doses in mice, inducing tremors, seizures, and even death (41). The nAChRs are allosteric membrane proteins that belong to a large family of ligand-gated ion channels. Each receptor is composed of a combination of five subunits. To date, 12 neuronal subunits (␣2-␣10 and ␤2-␤4) have been identified (reviewed in Ref. 29). They are widely distributed in the central and peripheral nervous systems and are also expressed in nonneuronal cells (11,14,23,30,37).In humans, nAChRs are associated with a number of pathological conditions, including epilepsy (reviewed in Ref. 35). Mutations in the ␣4-and ␤2-subunit genes were associated with familial cases of autosomal dominant nocturnal frontal lobe epilepsy (15, 45, 52-54). In addition, genetic linkage was found between juvenile myoclonic epilepsy and the chromosomal region encompassing the ␣7-subunit gene (18).In mice, a genetic linkage was shown betw...

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4*Nicotinic Receptors

“…Because higher nicotine doses are required, we speculate that different nAChR subtypes are activated (and or desensitized) during WT seizures. Indeed, studies on knock-out mice indicate that other nicotinic subunits (␣3, ␣5, and ␤4) are more important than those containing ␣4 in mediating nicotine seizures in WT (Kedmi et al, 2004;Salas et al, 2004). Although there are no published reports on the nicotineinduced seizure phenotype of ␣4 knock-out mice, we recently found that these mice are similar to their WT littermates in their sensitivity to nicotine seizures (our unpublished data).…”

Decreased Signs of Nicotine Withdrawal in Mice Null for the β4 Nicotinic Acetylcholine Receptor Subunit

“…␣3 heterozygous and ␣5 null mice have a phenotype similar to that of ␤4 Ϫ/Ϫ mutants in that they are less sensitive to acute nicotine than controls (Salas et al, 2003b(Salas et al, , 2004Kedmi et al, 2004). In addition, the ␣3 and ␣5 subunits are coexpressed with ␤4 in the MHb, the IPN, and peripheral ganglia.…”

“…Examples are as follows: the involvement of ␣4 in nicotine-dependent antinociception (Marubio et al, 1999), ␣4, ␤3, and ␤4 in anxiety-related behaviors (Booker et al, 2000;Ross et al, 2000;Salas et al, 2003a), ␤2 in fear conditioning and cocaine-induced nicotine selfadministration (Picciotto et al, 1998), ␣7 in neuronal protection (Laudenbach et al, 2002), and ␣3, ␣5, and ␤4 in nicotineinduced seizures (Salas et al, 2003b(Salas et al, , 2004Kedmi et al, 2004).…”

Structural and functional diversity of native brain neuronal nicotinic receptors

“…Deletion of thesubunit reduces the high affinity agonist activation of presynaptic nAChRs in the striatum and thalamus without altering their number, and these results indicate that the primary effect of  incorporation is to increase nAChR function without affecting nAChR expression, which may explain why α5 Ko mice are less sensitive to the acute effects of nicotine administration [59,60].…”