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Vol. 61, Issue 3, 695-705, March 2002
7 Nicotinic Acetylcholine Receptor Mutation
Division of Neuroscience (R.S.B., R.S., D.J., R.P., J.W.P., J.A.D.,
M.D.B.) and Department of Molecular and Human Genetics (R.P.), Baylor
College of Medicine, Houston, Texas
High doses of nicotine, the addictive component of tobacco, induce
clonic-tonic seizures in animals. Pharmacological and biochemical data
have suggested that 
7-containing neuronal nicotinic receptors (nAChRs) contribute to these seizures. To study potential 7
contributions, we examined 7 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 7
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 7-type currents with
increased amplitudes and slower desensitization kinetics, confirming a
partial gain of function for the 7 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 7 nAChR protein levels. There were
no changes in the levels of 4, 5, 6, 7, 
2, and 4
mRNA, or in [125I]epibatidine and
[3H]nicotine binding between +/T and +/+ mice. Recent
data from our laboratory show that 7-null mice maintain normal
sensitivity to nicotine-induced seizures. Hence, these present findings
suggest that alterations in the properties rather than absence of 7
nAChRs might affect the mechanisms underlying the convulsive properties of nicotine.
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