Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease

Timothy F. Musial, Elizabeth Molina-Campos, Linda A. Bean, Natividad Ybarra, Ronen Borenstein, Matthew L. Russo, Eric W. Buss, Daniel Justus, Krystina M. Neuman, Gelique D. Ayala, Sheila A. Mullen, Yuliya Voskobiynyk, Christopher T. Tulisiak, Jasmine A. Fels, Nicola J. Corbett, Gabriel Carballo, Colette D. Kennedy, Jelena Popovic, Josefina Ramos-Franco, Michael Fill & 13 others Melissa R. Pergande, Jeffrey A. Borgia, Grant T. Corbett, Kalipada Pahan, Ye Han, Dane M. Chetkovich, Robert J Vassar, Richard W. Byrne, M. Matthew Oh, Travis R. Stoub, Stefan Remy, John F Disterhoft*, Daniel A. Nicholson

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)141-157
Number of pages17
JournalNeurobiology of Learning and Memory
Volume154
DOIs
StatePublished - Oct 1 2018

Fingerprint

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Channelopathies
Alzheimer Disease
Cyclic Nucleotides
Nervous System Diseases
Endoplasmic Reticulum
Transgenic Mice
Pyramidal Cells
Drug Delivery Systems
Ion Channels
Pharmacology
Neurons

Keywords

  • Array tomography
  • Carvedilol
  • Electron microscopy
  • Endoplasmic reticulum
  • HCN channel
  • Patch-clamp
  • TRIP8b

ASJC Scopus subject areas

  • Experimental and Cognitive Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

Cite this

Musial, T. F., Molina-Campos, E., Bean, L. A., Ybarra, N., Borenstein, R., Russo, M. L., ... Nicholson, D. A. (2018). Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease. Neurobiology of Learning and Memory, 154, 141-157. https://doi.org/10.1016/j.nlm.2018.06.004
Musial, Timothy F. ; Molina-Campos, Elizabeth ; Bean, Linda A. ; Ybarra, Natividad ; Borenstein, Ronen ; Russo, Matthew L. ; Buss, Eric W. ; Justus, Daniel ; Neuman, Krystina M. ; Ayala, Gelique D. ; Mullen, Sheila A. ; Voskobiynyk, Yuliya ; Tulisiak, Christopher T. ; Fels, Jasmine A. ; Corbett, Nicola J. ; Carballo, Gabriel ; Kennedy, Colette D. ; Popovic, Jelena ; Ramos-Franco, Josefina ; Fill, Michael ; Pergande, Melissa R. ; Borgia, Jeffrey A. ; Corbett, Grant T. ; Pahan, Kalipada ; Han, Ye ; Chetkovich, Dane M. ; Vassar, Robert J ; Byrne, Richard W. ; Matthew Oh, M. ; Stoub, Travis R. ; Remy, Stefan ; Disterhoft, John F ; Nicholson, Daniel A. / Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease. In: Neurobiology of Learning and Memory. 2018 ; Vol. 154. pp. 141-157.
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abstract = "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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Musial, TF, Molina-Campos, E, Bean, LA, Ybarra, N, Borenstein, R, Russo, ML, Buss, EW, Justus, D, Neuman, KM, Ayala, GD, Mullen, SA, Voskobiynyk, Y, Tulisiak, CT, Fels, JA, Corbett, NJ, Carballo, G, Kennedy, CD, Popovic, J, Ramos-Franco, J, Fill, M, Pergande, MR, Borgia, JA, Corbett, GT, Pahan, K, Han, Y, Chetkovich, DM, Vassar, RJ, Byrne, RW, Matthew Oh, M, Stoub, TR, Remy, S, Disterhoft, JF & Nicholson, DA 2018, 'Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease', Neurobiology of Learning and Memory, vol. 154, pp. 141-157. https://doi.org/10.1016/j.nlm.2018.06.004

Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease. / Musial, Timothy F.; Molina-Campos, Elizabeth; Bean, Linda A.; Ybarra, Natividad; Borenstein, Ronen; Russo, Matthew L.; Buss, Eric W.; Justus, Daniel; Neuman, Krystina M.; Ayala, Gelique D.; Mullen, Sheila A.; Voskobiynyk, Yuliya; Tulisiak, Christopher T.; Fels, Jasmine A.; Corbett, Nicola J.; Carballo, Gabriel; Kennedy, Colette D.; Popovic, Jelena; Ramos-Franco, Josefina; Fill, Michael; Pergande, Melissa R.; Borgia, Jeffrey A.; Corbett, Grant T.; Pahan, Kalipada; Han, Ye; Chetkovich, Dane M.; Vassar, Robert J; Byrne, Richard W.; Matthew Oh, M.; Stoub, Travis R.; Remy, Stefan; Disterhoft, John F; Nicholson, Daniel A.

In: Neurobiology of Learning and Memory, Vol. 154, 01.10.2018, p. 141-157.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease

AU - Musial, Timothy F.

AU - Molina-Campos, Elizabeth

AU - Bean, Linda A.

AU - Ybarra, Natividad

AU - Borenstein, Ronen

AU - Russo, Matthew L.

AU - Buss, Eric W.

AU - Justus, Daniel

AU - Neuman, Krystina M.

AU - Ayala, Gelique D.

AU - Mullen, Sheila A.

AU - Voskobiynyk, Yuliya

AU - Tulisiak, Christopher T.

AU - Fels, Jasmine A.

AU - Corbett, Nicola J.

AU - Carballo, Gabriel

AU - Kennedy, Colette D.

AU - Popovic, Jelena

AU - Ramos-Franco, Josefina

AU - Fill, Michael

AU - Pergande, Melissa R.

AU - Borgia, Jeffrey A.

AU - Corbett, Grant T.

AU - Pahan, Kalipada

AU - Han, Ye

AU - Chetkovich, Dane M.

AU - Vassar, Robert J

AU - Byrne, Richard W.

AU - Matthew Oh, M.

AU - Stoub, Travis R.

AU - Remy, Stefan

AU - Disterhoft, John F

AU - Nicholson, Daniel A.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

KW - Array tomography

KW - Carvedilol

KW - Electron microscopy

KW - Endoplasmic reticulum

KW - HCN channel

KW - Patch-clamp

KW - TRIP8b

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U2 - 10.1016/j.nlm.2018.06.004

DO - 10.1016/j.nlm.2018.06.004

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JO - Neurobiology of Learning and Memory

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