Genetic deletion of a7 nAChRs reduces hippocampal granule and pyramidal cell number in both sexes but impairs pattern separation in males only

IntroductionNeurogenesis within the dentate gyrus is thought to play an important role in cognitive processes such as reversal learning and pattern separation. The & alpha;7 nicotinic acetylcholine receptor (& alpha;7 nAChR) is expressed early in newly formed granule cells of the dentate gyrus, though its role in neurogenesis and related cognitive function is not fully understood.MethodsTo better characterize relevant function of & alpha;7 nAChRs, we performed unbiased stereology to quantify hippocampal granule cells, pyramidal cells, and total volume and used a touchscreen operant spatial discrimination/reversal task to test pattern separation in a global & alpha;7 nAChR knockout mouse line.ResultsThe knockout resulted in an & AP;22% reduction in granule cells and a & AP; 20% reduction in pyramidal cells in both sexes, with no change in total hippocampal volume. However, the knockout impaired performance in the touchscreen task for males only. The sex-dependent difference in behavioral, but not stereological, results suggest a divergence in the structure-function relationship in males versus females. Detailed analyses revealed males were more biased by the initial reversal contingency relative to females indicating a potential source of the sex-specific interaction with the loss of & alpha;7 nAChRs.DiscussionThese findings argue that the & alpha;7 nAChR plays a critical role in hippocampal development, not just granule cell neurogenesis, and plays a sex-dependent role in cognitive function.