TY - JOUR T1 - FGF-23-deficiency impairs hippocampal-dependent cognitive function JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0469-18.2019 SP - ENEURO.0469-18.2019 AU - Ann M. Laszczyk AU - Dailey Nettles AU - Tate A. Pollock AU - Stephanie Fox AU - Melissa L. Garcia AU - Jing Wang AU - L. Darryl Quarles AU - Gwendalyn D. King Y1 - 2019/03/07 UR - http://www.eneuro.org/content/early/2019/03/07/ENEURO.0469-18.2019.abstract N2 - Fibroblast growth factor receptor and α-Klotho transduce fibroblast growth factor 23 (FGF-23) signaling in renal tubules to maintain systemic phosphate/Vitamin D homeostasis. Mice deficient for either the ligand, FGF-23, or the co-receptor, Klotho, are phenocopies with both showing rapid and premature development of multiple aging-like abnormalities. Such similarity in phenotype, suggests that FGF-23 and Klotho have co-dependent systemic functions. Recent reports revealed inverse central nervous system effects of Klotho deficiency or Klotho overexpression on hippocampal synaptic, neurogenic, and cognitive functions. However, it is unknown whether FGF-23 deficiency effects function of the hippocampus. We report that, similar to Klotho-deficient mice, FGF-23-deficient mice develop dose-dependent, hippocampal-dependent cognitive impairment. However, FGF-23-deficient brains had no gross structural or developmental defects, no change in hippocampal synaptic plasticity, and only minor impairment to postnatal hippocampal neurogenesis. Together these data provide evidence that FGF-23 deficiency impairs hippocampal-dependent cognition but otherwise results in a brain phenotype that is distinct from the KL-deficient mouse.Significance Statement Although FGF-23 is reportedly expressed by the brain, it has no known brain function. In the periphery, kidney transduction of FGF-23 signaling is required for proper phosphate, calcium and Vitamin D homeostasis. Recent reports show that Klotho, the obligate FGF-23 co-receptor, is required for multiple hippocampal activities. If Klotho-deficient brain effects are the result of disrupted FGF-23 signaling, similar phenotypes may occur under conditions of FGF-23 deficiency. Herein, studies were undertaken to determine whether FGF-23-deficient mice show impairment of the same hippocampal functions, as a first step toward investigating whether FGF-23 is the mechanism by which Klotho effects brain function. Our data show that FGF-23 is only required for normal hippocampal-dependent cognition suggesting that FGF-23 may effect the brain uniquely. ER -