Genetic deletion of α7 nAChRs reduces hippocampal granule and pyramidal cell number in both sexes but impairs pattern separation in males only.

Introduction: Neurogenesis within the dentate gyrus is thought to play an important role in cognitive processes such as reversal learning and pattern separation. The α7 nicotinic acetylcholine receptor (α7 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. Methods: To better characterize relevant function of α7 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 α7 nAChR knockout mouse line. Results: The knockout resulted in an ≈22% reduction in granule cells and a ≈ 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 α7 nAChRs. Discussion: These findings argue that the α7 nAChR plays a critical role in hippocampal development, not just granule cell neurogenesis, and plays a sex-dependent role in cognitive function.

Loss of α7 nicotinic acetylcholine receptors in GABAergic neurons causes sex-dependent decreases in radial glia-like cell quantity and impairments in cognitive and social behavior.

The dentate gyrus (DG) is a unique brain structure in that neurons can be generated postnatally and integrated within existing circuitry throughout life. The maturation process of these newly generated neurons (granule cells) is modulated by nicotinic acetylcholine receptors (nAChRs) through a variety of mechanisms such as neural stem pool proliferation, cell survival, signal modulation, and dendritic integration. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, predominantly the α7 subtype, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined histological and behavioral effects of knocking out α7 nAChRs in GABAergic neurons. Deletion of α7 nAChRs resulted in a reduction of radial glia-like cells within the subgranular zone of the DG and a concomitant trend towards decreased immature neurons, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition and spatial learning. Overall, these findings suggest α7 nAChRs expressed in GABAergic neurons play an important role in regulating the adult neural stem cell pool and behavior in a sex-dependent manner. This provides important insight into the mechanisms by which cholinergic dysfunction contributes to the cognitive and behavioral changes associated with neurodevelopmental and neurodegenerative disorders.