Loss of α7 nicotinic acetylcholine receptors in GABAergic interneurons causes sex-dependent impairments in postnatal neurogenesis and cognitive and social behavior

Abstract

Neural stem cells within the subgranular zone of the dentate gyrus (DG) generate new neurons that form the granule cell layer during embryonic development and continue to generate new neurons throughout life. The maturation process of newly generated granule cells is modulated by nicotinic acetylcholine receptors (nAChRs), which have been shown to play a role in cell survival, signal modulation, dendritic integration, and memory formation. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, particularly the 7 subunit, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined the effects of conditional deletion of 7 nAChRs in GABAergic interneurons on measures of postnatal neurogenesis and behavioral outcomes. Loss of 7 nAChRs resulted in a decrease of postnatal granule cells, as indicated by reduced GFAP+ cells in the DG, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition, object investigation, and spatial learning. Overall, these findings suggest 7 nAChRs expressed in GABAergic interneurons play an important role in regulating postnatal neurogenesis 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.