Editors' ChoiceNeuroscience

Strong Bones for a Strong Mind

Science Signaling  01 Oct 2013:
Vol. 6, Issue 295, pp. ec234
DOI: 10.1126/scisignal.2004766

Osteocalcin is a hormone secreted by osteoblasts that regulates diverse physiological processes, including metabolism and fertility. Oury et al. report that osteocalcin also inhibits depression and promotes learning and memory. Compared to wild-type littermates and to mice lacking Gprc6a, which encodes the receptor that mediates the metabolic effects of osteocalcin, mice lacking osteocalcin (Ocn–/– mice) showed decreased locomotion and altered abundance of several neurotransmitters. Specifically, the brains of Ocn–/– mice had decreased amounts of γ-aminobutyric acid (GABA) and increased amounts of serotonin, norepinephrine, and dopamine and showed corresponding changes in the expression of genes required for the biosynthesis of each of these neurotransmitters. Behavioral testing revealed that Ocn–/– mice exhibited symptoms of anxiety and depression and showed an inability to learn in a spatial memory test, whereas Gprc6a–/– mice performed as well as wild-type mice. In vivo, osteocalcin crossed the blood-brain barrier and bound to neurons in various parts of the brain. Application of osteocalcin to brain slices decreased expression of a gene required for GABA biosynthesis and increased expression of genes required for serotonin, dopamine, and norepinephrine biosynthesis. Administering osteocalcin intracerebroventricularly to Ocn–/– mice for 1 week restored normal expression of neurotransmitter biosynthesis genes and improved the behavioral and learning deficits. In addition to being required for normal postnatal brain development, osteocalcin was also required maternally for fetal brain development. Most of the circulating osteocalcin present in developing embryos derived from the mother, and the brains of embryos from Ocn–/– mothers showed malformations, reduced mass, and increased neuronal apoptosis. The behavioral and learning phenotypes of Ocn–/– mice born to Ocn–/– mothers were more severe than those of Ocn–/– mice born to Ocn+/– mothers. It has been established that brain-derived leptin influences bone mass, and now it also appears that bones can influence brain development and function.

F. Oury, L. Khrimian, C. A. Denny, A. Gardin, A. Chamouni, N. Goeden, Y.-y. Huang, H. Lee, P. Srinivas, X.-B. Gao, S. Suyama, T. Langer, J. J. Mann, T. L. Horvath, A. Bonnin, G. Karsenty, Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155, 228–241 (2013). [PubMed]

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