Maternal and Offspring Pools of Osteocalcin Influence Brain Development and Functions

• Published in: Cell 2013-09, Vol.155 (1), p.228-241
• Main Authors: Oury, Franck, Khrimian, Lori, Denny, Christine A., Gardin, Antoine, Chamouni, Alexandre, Goeden, Nick, Huang, Yung-yu, Lee, Hojoon, Srinivas, Prashanth, Gao, Xiao-Bing, Suyama, Shigetomo, Langer, Thomas, Mann, John. J., Horvath, Tamas L., Bonnin, Alexandre, Karsenty, Gerard
• Format: Article
• Language: English
• Subjects: Aging; Animals; anxiety; apoptosis; blood-brain barrier; bone density; Brain - embryology; Brain - growth & development; Brain - physiology; brain stem; cognition; crossing; Female; Fetus - metabolism; gamma-aminobutyric acid; genotype; hippocampus; hormones; memory; Mice; mothers; neurons; Neurotransmitter Agents - metabolism; neurotransmitters; osteocalcin; Osteocalcin - metabolism; placenta; Pregnancy; progeny; Signal Transduction; skeleton
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.08.042

The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain, and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression, and favors learning and memory independently of its metabolic functions. In addition to these postnatal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result, the severity of the neuroanatomical defects and learning and memory deficits of Osteocalcin−/− mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin−/− mothers rescues these abnormalities in their Osteocalcin−/− progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development. [Display omitted] •Osteocalcin signals in the brain and favors postnatal neurogenesis•Osteocalcin prevents anxiety and depression and favors memory•Maternal osteocalcin crosses the placenta and favors fetal brain development•Maternal osteocalcin influences spatial learning and memory in adult offspring Osteocalcin is a hormone produced in the skeleton that is able to traverse the blood-brain barrier to regulate brain development and adult neurogenesis as well as control complex behaviors.