12321 The Neurotransmitter Glutamate Promotes The Endocrine Functions Of Bone

• Published in: Journal of the Endocrine Society Vol. 8; no. Supplement_1
• Main Authors: Delgado, I Canal, Romeo-Guitart, D, Oury, F, Karsenty, G
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 05.10.2024
• Subjects: Abstract; Cognition & reasoning
• ISSN: 2472-1972; 2472-1972
• DOI: 10.1210/jendso/bvae163.514

Abstract Disclosure: I. Canal Delgado: None. G. Karsenty: None. The osteoblast-derived hormone osteocalcin must be decarboxylated to become active. This can be achieved by neurite-derived glutamate, which once in osteoblasts, inhibits the enzyme responsible of osteocalcin carboxylation. Glutamate enters osteoblasts through the EAAT1/Glast transporter, a gene highly expressed in glial cells but whose functions in peripheral organs has not been systematically investigated. To precisely define the functions of glutamate in osteoblasts, we generated mice lacking Glast only in osteoblasts (Glastosb-/-). We first observed that deleting Glast from osteoblasts decreased circulating levels of the uncarboxylated and active form of osteocalcin. Phenotypic analysis showed that Glastosb-/- mice experience a much weaker acute stress response following exposure to a physical stressor, are hyperglycemic and hypoinsulinemic compared to wild-type (WT) littermates. These abnormalities are the ones seen in mice lacking osteocalcin and were corrected by exogenous osteocalcin. We next used this mutant mouse strain as a tool to ask whether any of the symptoms observed in GLAST-deficient patients might be due, in part, to the absence of glutamate signaling in osteoblasts. We focused on cognition because this central function is impaired in GLAST-deficient subjects, and it is regulated by osteocalcin. We observed that Glastosb-/- mice had a severe cognitive impairment. To define more precisely the contribution of bone to the cognitive defect caused by the absence of GLAST, we relied on both pharmacological and genetic experiments. First, we treated WT mice with a Glast inhibitor that does not cross the blood-brain barrier (BBB) and therefore, does not affect any brain structure, or with another Glast inhibitor that crosses the BBB. In the conditions of this experiment, only the Glast inhibitor that does not cross the BBB impaired cognition in WT mice, further suggesting that glutamate signaling regulates behavior in part by regulating the release of active osteocalcin from bone. To strengthen these results, we are currently comparing cognition functions in mutant mice lacking Glast in glial cells or neurons. Together, our observations illustrate the important functions played by of glutamate in osteoblasts and suggest that some behavioral phenotype caused by the absence of GLAST in humans may originate, at least in part, from the disruption of glutamate signaling in the skeleton. Presentation: 6/2/2024