Store depletion-inducedh-channel plasticity rescues a channelopathy linked to Alzheimer’s disease


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Abstract

HIGHLIGHTSAccommodation at perithreshold currents is exacerbated with age in CA1 neurons of ADTg mice.HCN1 is sequestered perisomatically in aged ADTg mice.HCN1 is sequestered as a multimolecular complex with TRIP8b in aged ADTg mice.Ex vivo and in vivo SDh plasticity rescue HCN channel function/mislocalization.Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer’s disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.

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