. 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. J Neurosci. 2015 Jul 29;35(30):10878-87. PubMed.


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  1. This is an interesting and elegant study that further supports the connection between excessive ryanodine receptor (RyanR)-mediated calcium release from neuronal endoplasmic reticulum (ER) and memory defects in aging and AD. The authors demonstrate here that AAV-mediated overexpression of FKBP1b protein in hippocampus of aged rats reduced RyanR-mediated calcium release, inhibited afterhyperpolarizatin (AHP), and improved performance in memory assays. Remarkably, they observed a quantitative correlation between slow AHP duration and memory performance in these experiments (Fig 5). Previous studies suggested that excessive RyanR-mediated Ca2+ release and enhanced AHP may contribute to synaptic plasticity defects in a presenilin knock-in model of AD (Zhang et al., 2015; Chakroborty et al., 2012). Non-selective RyanR inhibitor dantrolene and SK channel inhibitor Apamin was used in these studies to correct calcium signaling and plasticity defects in PS1 KI mice (Zhang et al., 2015; Chakroborty et al., 2012). Results in the paper by Gant at al. suggest that enhanced expression of FKBP1b protein may also be used as therapeutic strategy to correct dysregulated RyanR-mediated ER Ca2+ signaling and memory defects in aging and AD brains.


    . Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2015;45(2):561-80. PubMed.

    . Early presynaptic and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer's disease mice. J Neurosci. 2012 Jun 13;32(24):8341-53. PubMed.

  2. Gant et al.'s study taps into a growing and persistent theme in aging and AD research by demonstrating how dysregulated calcium signaling contributes to mechanisms underlying memory decline. Their key finding shows that increasing expression of a gene (FK506 BP12.6/1b) whose protein product regulates ryanodine receptor (RyR) calcium release restores not only activity-evoked calcium responses, but also slow afterhyperpolarization (sAHP) properties and spatial memory function in aged rats. Since this FK506BP regulatory protein declines with age, and with AD, the authors provide a much-needed molecular mechanism for the increased intracellular calcium release observed in aging and AD. By reversing the increased sAHP in aged animals via increasing FKBP12, the Landfield group also provides an important neurophysiological link to the molecular, calcium signaling, and behavioral data, which is a mechanistic step often skipped in the field. A question that remains is whether the reduced spike-evoked calcium responses seen in the transfected neurons reflects restoration to “normal” calcium levels, or if increasing the FK506BP suppresses calcium responses in general, and thus leads to the reduced AHP. Adding another younger cohort, perhaps in future studies, may provide more answers.

    In a broader context, this study adds another layer of evidence demonstrating how calcium dyshomeostasis can drive a broad array of aging and AD-related memory deficits. Additionally, it speaks to the growing understanding of how RyR-mediated calcium dynamics are integrated with a vast array of neuronal signaling processes under normal physiological conditions, thus providing a better framework for understanding how multiple seemingly disparate disease features can be linked to a single calcium signaling cascade. 

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