Calcium dysregulation via L-type voltage-dependent calcium channels and ryanodine receptors underlies memory deficits and synaptic dysfunction during chronic neuroinflammation

Sarah C Hopp, Heather M. D'Angelo, Sarah E. Royer, Roxanne M. Kaercher, Alexis M. Crockett, Linda Adzovic, Gary L. Wenk

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Chronic neuroinflammation and calcium (Ca+2) dysregulation are both components of Alzheimer's disease. Prolonged neuroinflammation produces elevation of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal Ca+2 homeostasis via L-type voltage-dependent Ca+2 channels (L-VDCCs) and ryanodine receptors (RyRs). Chronic neuroinflammation also leads to deficits in spatial memory, which may be related to Ca+2 dysregulation. Methods: The studies herein use an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28days. The rats were treated with the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene. Results: LPS-infused rats had significant memory deficits in the Morris water maze, and this deficit was ameliorated by treatment with nimodipine. Synaptosomes from LPS-infused rats had increased Ca+2 uptake, which was reduced by a blockade of L-VDCCs either in vivo or ex vivo. Conclusions: Taken together, these data indicate that Ca+2 dysregulation during chronic neuroinflammation is partially dependent on increases in L-VDCC function. However, blockade of the RyRs also slightly improved spatial memory of the LPS-infused rats, demonstrating that other Ca+2 channels are dysregulated during chronic neuroinflammation. Ca+2-dependent immediate early gene expression was reduced in LPS-infused rats treated with dantrolene or nimodipine, indicating normalized synaptic function that may underlie improvements in spatial memory. Pro-inflammatory markers are also reduced in LPS-infused rats treated with either drug. Overall, these data suggest that Ca+2 dysregulation via L-VDCCs and RyRs play a crucial role in memory deficits resulting from chronic neuroinflammation.

Original languageEnglish (US)
Article number56
JournalJournal of Neuroinflammation
Volume12
Issue number1
DOIs
StatePublished - Mar 25 2015
Externally publishedYes

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Calcium-Sensing Receptors
L-Type Calcium Channels
Ryanodine Receptor Calcium Release Channel
Memory Disorders
Lipopolysaccharides
Calcium
Nimodipine
Dantrolene
Immediate-Early Genes
Synaptosomes
Cerebrospinal Fluid
Reactive Oxygen Species
Alzheimer Disease
Homeostasis
Cytokines
Gene Expression
Water
Pharmaceutical Preparations

Keywords

  • Calcium
  • L-type voltage-dependent calcium channels
  • Neuroinflammation
  • Ryanodine receptors
  • Spatial memory

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Calcium dysregulation via L-type voltage-dependent calcium channels and ryanodine receptors underlies memory deficits and synaptic dysfunction during chronic neuroinflammation. / Hopp, Sarah C; D'Angelo, Heather M.; Royer, Sarah E.; Kaercher, Roxanne M.; Crockett, Alexis M.; Adzovic, Linda; Wenk, Gary L.

In: Journal of Neuroinflammation, Vol. 12, No. 1, 56, 25.03.2015.

Research output: Contribution to journalArticle

Hopp, Sarah C ; D'Angelo, Heather M. ; Royer, Sarah E. ; Kaercher, Roxanne M. ; Crockett, Alexis M. ; Adzovic, Linda ; Wenk, Gary L. / Calcium dysregulation via L-type voltage-dependent calcium channels and ryanodine receptors underlies memory deficits and synaptic dysfunction during chronic neuroinflammation. In: Journal of Neuroinflammation. 2015 ; Vol. 12, No. 1.
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AU - Hopp, Sarah C

AU - D'Angelo, Heather M.

AU - Royer, Sarah E.

AU - Kaercher, Roxanne M.

AU - Crockett, Alexis M.

AU - Adzovic, Linda

AU - Wenk, Gary L.

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AB - Background: Chronic neuroinflammation and calcium (Ca+2) dysregulation are both components of Alzheimer's disease. Prolonged neuroinflammation produces elevation of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal Ca+2 homeostasis via L-type voltage-dependent Ca+2 channels (L-VDCCs) and ryanodine receptors (RyRs). Chronic neuroinflammation also leads to deficits in spatial memory, which may be related to Ca+2 dysregulation. Methods: The studies herein use an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28days. The rats were treated with the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene. Results: LPS-infused rats had significant memory deficits in the Morris water maze, and this deficit was ameliorated by treatment with nimodipine. Synaptosomes from LPS-infused rats had increased Ca+2 uptake, which was reduced by a blockade of L-VDCCs either in vivo or ex vivo. Conclusions: Taken together, these data indicate that Ca+2 dysregulation during chronic neuroinflammation is partially dependent on increases in L-VDCC function. However, blockade of the RyRs also slightly improved spatial memory of the LPS-infused rats, demonstrating that other Ca+2 channels are dysregulated during chronic neuroinflammation. Ca+2-dependent immediate early gene expression was reduced in LPS-infused rats treated with dantrolene or nimodipine, indicating normalized synaptic function that may underlie improvements in spatial memory. Pro-inflammatory markers are also reduced in LPS-infused rats treated with either drug. Overall, these data suggest that Ca+2 dysregulation via L-VDCCs and RyRs play a crucial role in memory deficits resulting from chronic neuroinflammation.

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KW - Ryanodine receptors

KW - Spatial memory

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