Increased sensitivity to nicotine-induced seizures in mice expressing the L250T alpha 7 nicotinic acetylcholine receptor mutation

High doses of nicotine, the addictive component of tobacco, induce clonic-tonic seizures in animals. Pharmacological and biochemical data have suggested that alpha7-containing neuronal nicotinic receptors (nAChRs) contribute to these seizures. To study potential alpha7 contributions, we examined alpha7 subunits with a Leu250-to-Thr substitution in the channel domain, which creates a gain-of-function mutation. Previous studies have shown that mice homozygous for the alpha7 L250T mutation (T/T) die shortly after birth, but animals heterozygous for the mutation (+/T) are viable and grow to adulthood. Hippocampal neurons from the +/T mice exhibited altered alpha7-type currents with increased amplitudes and slower desensitization kinetics, confirming a partial gain of function for the alpha7 nAChR. We found that +/T mice were more sensitive to the convulsant effects of nicotine compared with their wild-type (+/+) littermates. Furthermore, although their behavior was normal in basal conditions, +/T mice showed a unique nicotine-induced phenotype, consisting of head-bobbing and paw-tapping movements. Increased sensitivity to nicotine-induced seizures occurred despite a 60% decline in brain alpha7 nAChR protein levels. There were no changes in the levels of alpha4, alpha5, alpha6, alpha7, beta2, and beta4 rnRNA, or in [I-125]epibatidine and [H-3]nicotine binding between +/T and +/+ mice. Recent data from our laboratory show that alpha7-null mice maintain normal sensitivity to nicotine-induced seizures. Hence, these present findings suggest that alterations in the properties rather than absence of alpha7 nAChRs might affect the mechanisms underlying the convulsive properties of nicotine.