Disrupting function of FK506-binding protein 1b/12.6 induces the Ca 2+-dysregulation aging phenotype in hippocampal neurons

John C. Gant, Kuey Chu Chen, Christopher M. Norris, Inga Kadish, Olivier Thibault, Eric M. Blalock, Nada M. Porter, Philip W. Landfield

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

With aging, multiple Ca2+-associated electrophysiological processes exhibit increased magnitude in hippocampal pyramidal neurons, including the Ca2+-dependent slow afterhyperpolarization (sAHP), L-type voltage-gated Ca2+ channel (L-VGCC) activity, Ca 2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs), and Ca2+ transients. This pattern of Ca2+ 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 up-regulated with aging in rats. Here, we tested the hypothesis that disrupting FKBP1b function also destabilizes Ca2+ homeostasis in hippocampal neurons and is sufficient to induce the aging phenotype of Ca2+ 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 Ca2+-dysregulation aging phenotype in young rat hippocampus, supporting a novel hypothesis that declining FKBP function plays a major role in unhealthy brain aging.

Original languageEnglish
Pages (from-to)1693-1703
Number of pages11
JournalJournal of Neuroscience
Volume31
Issue number5
DOIs
StatePublished - Feb 2 2011

ASJC Scopus subject areas

  • Medicine (all)

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