title: Disrupting function of FK506-binding protein 1b/12.6 induces the Ca²+-dysregulation aging phenotype in hippocampal neurons.
abstract: With aging, multiple Ca(2+)-associated electrophysiological processes exhibit increased magnitude in hippocampal pyramidal neurons, including the Ca(2+)-dependent slow afterhyperpolarization (sAHP), L-type voltage-gated Ca(2+) channel (L-VGCC) activity, Ca(2+)-induced Ca(2+) release (CICR) from ryanodine receptors (RyRs), and Ca(2+) transients. This pattern of Ca(2+) dysregulation correlates with reduced neuronal excitability/plasticity and impaired learning/memory and has been proposed to contribute to unhealthy brain aging and Alzheimer's disease. However, little is known about the underlying molecular mechanisms. In cardiomyocytes, FK506-binding protein 1b/12.6 (FKBP1b) binds and stabilizes RyR2 in the closed state, inhibiting RyR-mediated Ca(2+) release. Moreover, we recently found that hippocampal Fkbp1b expression is downregulated, whereas Ryr2 and Frap1/Mtor (mammalian target of rapamycin) expression is upregulated with aging in rats. Here, we tested the hypothesis that disrupting FKBP1b function also destabilizes Ca(2+) homeostasis in hippocampal neurons and is sufficient to induce the aging phenotype of Ca(2+) dysregulation in young animals. Selective knockdown of Fkbp1b with interfering RNA in vitro (96 h) enhanced voltage-gated Ca(2+) current in cultured neurons, whereas in vivo Fkbp1b knockdown by microinjection of viral vector (3-4 weeks) dramatically increased the sAHP in hippocampal slice neurons from young-adult rats. Rapamycin, which displaces FKBP1b from RyRs in myocytes, similarly enhanced VGCC current and the sAHP and also increased CICR. Moreover, FKBP1b knockdown in vivo was associated with upregulation of RyR2 and mTOR protein expression. Thus, disruption of FKBP1b recapitulated much of the Ca(2+)-dysregulation aging phenotype in young rat hippocampus, supporting a novel hypothesis that declining FKBP function plays a major role in unhealthy brain aging.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, Kentucky 40536-0298, USA. cgant@uky.edu
authors.forename: John C
authors.initials: JC
authors.lastname: Gant
authors.forename: Kuey-Chu
authors.initials: KC
authors.lastname: Chen
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Norris
authors.forename: Inga
authors.initials: I
authors.lastname: Kadish
authors.forename: Olivier
authors.initials: O
authors.lastname: Thibault
authors.forename: Eric M
authors.initials: EM
authors.lastname: Blalock
authors.forename: Nada M
authors.initials: NM
authors.lastname: Porter
authors.forename: Philip W
authors.initials: PW
authors.lastname: Landfield
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D004594:Electrophysiology; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D006706:Homeostasis / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D017966:Pyramidal Cells / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D011916:Rats, Inbred F344; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; C557049:FKBP1b protein, rat; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D002118:Calcium; D020123:Sirolimus