Osteocalcin in the brain: from embryonic development to age-related decline in cognition

Abstract

A remarkable, unexpected aspect of the bone-derived hormone osteocalcin is that it is necessary for both brain development and brain function in the mouse, as its absence results in a profound deficit in spatial learning and memory and an exacerbation of anxiety-like behaviour. The regulation of cognitive function by osteocalcin, together with the fact that its circulating levels decrease in midlife compared with adolescence in all species tested, raised the prospect that osteocalcin might be an anti-geronic hormone that could prevent age-related cognitive decline. As presented in this Review, recent data indicate that this is indeed the case and that osteocalcin is necessary for the anti-geronic activity recently ascribed to the plasma of young wild-type mice. The diversity and amplitude of the functions of osteocalcin in the brain, during development and postnatally, had long called for the identification of its receptor in the brain, which was also recently achieved. This Review presents our current understanding of the biology of osteocalcin in the brain, highlighting the bony vertebrate specificity of the regulation of cognitive function and pointing toward where therapeutic opportunities might exist.

Figure 1. Osteocalcin functions in peripheral organs

Schematic representation of the physiological functions regulated by osteocalcin.

Figure 2. Osteocalcin promotes spatial learning and memory and prevent anxiety-like behavior

Osteocalcin is made in bone, uses the general circulation to cross the blood brain barrier (BBB) and then binds neurons from the CA3 region of the hippocampus, the ventral tegmental area (VTA) of the midbrain, and dorsal raphe (DRN) and medial raphe (MRN) nuclei of the brainstem. Osteocalcin acts on these neurons through transcriptional events to increase the synthesis of all monoamines neurotransmitters and decrease that of GABA. Osteocalcin promotes spatial learning and memory and prevents anxiety-like behavior.

Figure 3. Maternal osteocalcin acts directly in the offspring to regulate embryonic brain development

Maternal osteocalcin crosses the placenta, promotes neurogenesis and prevents neuronal apoptosis in the hippocampal region of the offspring.

Figure 4. Osteocalcin is sufficient to improve cognition in aged mice

(a) Injections of plasma from young wild-type (WT) mice to aged WT mice improve memory performance and prevent anxiety-like behavior. This does not occur when plasma from young Osteocalcin-/- (Ocn-/-) mice is used instead of plasma from young WT mice. When Ocn-/- plasma is spiked with mouse recombinant osteocalcin, the ability of this plasma to improve cognitive functions is restored to same extend as when using plasma from young WT mice. (b) Plasma from young WT mice immunodepleted of osteocalcin cannot enhance cognition in aged mice.

Figure 5. Gpr158 pattern of expression in human tissues

Gpr158's pattern of expression obtained from the GTEX database (www.gtexportal.org).

Figure 6. Gpr158 mediates osteocalcin's functions in the brain

Osteocalcin binds Gpr158 in pyramidal neurons of the CA3 region of the hippocampus. This interaction promotes an increase in the accumulation of IP3 and BDNF in neurons.