ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2011
Disrupting function of FK506-binding protein 1b/12.6 induces the Ca²+-dysregulation aging phenotype in hippocampal neurons.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 56 citations in OpenAlex.
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- Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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- Role of lateral amygdala calstabin2 in regulation of fear memory.Molecular brain · 2020Article
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- Senescent neurophysiology: CaNeurobiology of learning and memory · 2019Review
- Network Models Predict That Pyramidal Neuron Hyperexcitability and Synapse Loss in the dlPFC Lead to Age-Related Spatial Working Memory Impairment in Rhesus Monkeys.Frontiers in computational neuroscience · 2019Article
- Neuronal Ryanodine Receptors in Development and Aging.Molecular neurobiology · 2018Review
- FK506-Binding Protein 12.6/1b, a Negative Regulator of [CaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer's Disease Neurofibrillary Tangles First Appear.Journal of Alzheimer's disease : JAD · 2018Article
- Novel calcium-related targets of insulin in hippocampal neurons.Neuroscience · 2017Article
- Intrinsic Hippocampal Excitability Changes of Opposite Signs and Different Origins in CA1 and CA3 Pyramidal Neurons Underlie Aging-Related Cognitive Deficits.Frontiers in systems neuroscience · 2016Review
- Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Integrative Transcriptome Profiling of Cognitive Aging and Its Preservation through Ser/Thr Protein Phosphatase Regulation.PloS one · 2015Article
- FK506-binding protein 1b/12.6: a key to aging-related hippocampal Ca2+ dysregulation?European journal of pharmacology · 2014Review
- Ryanodine receptors: physiological function and deregulation in Alzheimer disease.Molecular neurodegeneration · 2014Review
- Channelopathy pathogenesis in autism spectrum disorders.Frontiers in genetics · 2013Review
- Hippocampal calcium dysregulation at the nexus of diabetes and brain aging.European journal of pharmacology · 2013Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
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.
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