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; 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

doi:10.1016/j.nlm.2018.06.004

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 FillMelissa 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 journal › Article › peer-review

18 Scopus citations

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 language	English (US)
Pages (from-to)	141-157
Number of pages	17
Journal	Neurobiology of Learning and Memory
Volume	154
DOIs	https://doi.org/10.1016/j.nlm.2018.06.004
State	Published - Oct 2018

Funding

We thank Dr. Elliott Mufson and Dr. Sylvia Perez for generous provision of 3×Tg mice and help with amyloid staining. This research was funded by National Institute on Aging grants AG031574 , AG047073 , and AG050767 (to D.A.N.) and AG017139 (to D.A.N. and J.F.D.), and the Charles and M.R. Shapiro Foundation (to D.A.N.).

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

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Musial, T. F., Molina-Campos, E., Bean, L. A., Ybarra, N., Borenstein, R., Russo, M. L., Buss, E. W., Justus, D., Neuman, K. M., Ayala, G. D., Mullen, S. A., Voskobiynyk, Y., Tulisiak, C. T., Fels, J. A., Corbett, N. J., Carballo, G., Kennedy, C. D., Popovic, J., Ramos-Franco, J., ... 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

@article{9b7aca8dc3bc4765bcf3b8585a255863,

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

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.",

keywords = "Array tomography, Carvedilol, Electron microscopy, Endoplasmic reticulum, HCN channel, Patch-clamp, TRIP8b",

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

note = "Funding Information: We thank Dr. Elliott Mufson and Dr. Sylvia Perez for generous provision of 3×Tg mice and help with amyloid staining. This research was funded by National Institute on Aging grants AG031574 , AG047073 , and AG050767 (to D.A.N.) and AG017139 (to D.A.N. and J.F.D.), and the Charles and M.R. Shapiro Foundation (to D.A.N.). Publisher Copyright: {\textcopyright} 2018",

year = "2018",

month = oct,

doi = "10.1016/j.nlm.2018.06.004",

language = "English (US)",

volume = "154",

pages = "141--157",

journal = "Neurobiology of Learning and Memory",

issn = "1074-7427",

publisher = "Academic Press Inc.",

}

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

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.

N1 - Funding Information: We thank Dr. Elliott Mufson and Dr. Sylvia Perez for generous provision of 3×Tg mice and help with amyloid staining. This research was funded by National Institute on Aging grants AG031574 , AG047073 , and AG050767 (to D.A.N.) and AG017139 (to D.A.N. and J.F.D.), and the Charles and M.R. Shapiro Foundation (to D.A.N.). Publisher Copyright: © 2018

PY - 2018/10

Y1 - 2018/10

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

UR - http://www.scopus.com/inward/record.url?scp=85048835949&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048835949&partnerID=8YFLogxK

U2 - 10.1016/j.nlm.2018.06.004

DO - 10.1016/j.nlm.2018.06.004

M3 - Article

C2 - 29906573

AN - SCOPUS:85048835949

SN - 1074-7427

VL - 154

SP - 141

EP - 157

JO - Neurobiology of Learning and Memory

JF - Neurobiology of Learning and Memory

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

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