Brain‐specific deletion of M3 muscarinic acetylcholine receptor causes dwarfism in mice

The M 3 muscarinic acetylcholine (ACh) receptor (M 3 mAChR) is widely expressed throughout the brain and in many peripheral organs. Whereas the peripheral M 3 mAChRs are known to mediate many of the parasympathetic actions of ACh, the physiological significance of neuronal M 3 mAChRs remains unclear. To address this question, we generated mutant mice lacking M 3 mAChRs only in neurons and glial cells (‘brain‐M 3 ‐KO mice’). Brain‐M 3 ‐KO mice did not show any significant metabolic alterations, including energy consumption, food intake, and glucose homeostasis. However, adult brain‐M 3 ‐KO mice exhibited a dwarf‐like phenotype (∼10% reduction in body length and ∼20% decrease in body weight, as compared to control mice). Consistent with this phenotype, circulating IGF‐1 and growth hormone (GH) levels were significantly decreased in brain‐M 3 ‐KO mice. Moreover, histological analysis revealed a marked hypoplasia of the anterior pituitary gland of brain‐M 3 ‐KO mice, associated with greatly reduced pituitary GH and prolactin levels. We are currently testing the hypothesis that the lack of M 3 mAChRs that normally regulate the activity of hypothalamic GHRH neurons contributes to this phenotype. These studies reveal a critical and unexpected role for neuronal M 3 mAChRs in somatic growth and the proliferation of specific anterior pituitary cells.