Inbred mouse strains display significant differences in their levels of brain ␣7 nicotinic acetylcholine receptor (␣7 nAChR) expression, as measured by binding of the ␣7-selective antagonist ␣-bungarotoxin. Variations in ␣-bungarotoxin binding have been shown to correlate with an animal's sensitivity to nicotine-induced seizures and sensory gating. In two inbred mouse strains, C3H/2Ibg (C3H) and DBA/2Ibg (DBA/2), the interstrain binding differences are linked to a restriction length polymorphism in the ␣7 nAChR gene, Chrna7. Despite this finding, the molecular mechanism(s) through which genetic variability in Chrna7 may contribute to ␣7 nAChR expression differences remains unknown. However, studies of the human ␣7 nAChR gene (CHRNA7) previously have demonstrated that CHRNA7 promoter polymorphisms are associated with differences in promoter activity as well as differences in sensory processing. In the present study, a 947-base pair region of the Chrna7 promoter was cloned from both the C3H and DBA/2 inbred mouse strains in an attempt to identify polymorphisms that may underlie ␣7 nAChR differential expression. Sequence analysis of these fragments identified 14 single nucleotide polymorphisms (SNPs). A combination of two of these SNPs affects promoter activity in an in vitro luciferase reporter assay. These results suggest a mechanism through which the Chrna7 promoter genotype may influence interstrain variations in ␣7 nAChR expression.The expression of ␣7 nAChRs, 3 as measured by 125 I-labeled ␣-bungarotoxin (␣-BTX), varies significantly across inbred mouse strains (1, 2), and studies have demonstrated that interstrain differences in ␣7 nAChR expression are genetically regulated. For example, restriction fragment length polymorphisms in Chrna7, the gene that encodes for the mouse ␣7 nAChR subunit, have been shown to be linked to ␣7 nAChR expression in genetically segregating populations derived from the inbred mouse strains C3H and DBA/2 (3). The strain differences in binding appear to be related to differences in ␣7 nicotinic receptor mRNA levels (2, 4), suggesting that transcriptional or posttranscriptional mechanisms may contribute to the variations in ␣-BTX expression levels.Genetically regulated ␣7 nicotinic receptor expression patterns have been associated with individual variations in neurophysiology and neuroanatomy. Interstrain differences in ␣-BTX binding are related to variations in sensitivity to nicotine-induced seizures, acoustic startle response (5), and hippocampal sensory gating (2). In addition, genetic variability in Chrna7 has been implicated in regulating individual differences in cholinergic and GABAergic hippocampal neuroanatomy (6 -8).Variations in ␣-BTX binding have also been associated with differences in neurophysiological function among humans. Schizophrenics, for example, display reduced ␣-BTX binding levels in post-mortem hippocampus (9). Furthermore, promoter polymorphisms in the gene coding for the human ␣7 nAChR subunit are associated with an auditory gating deficit that is common...