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

Journal of Neuroinflammation

Gary L Wenk²  Linda Adzovic²  Alexis M Crockett²  Roxanne M Kaercher²  Sarah E Royer¹  Heather M D’Angelo²  Sarah C Hopp¹ 

[1] Departments of Neuroscience, Ohio State University, Columbus 43210, OH, USA;Department of Psychology, Ohio State University, 1835 Neil Ave, Columbus 43210, OH, USA

关键词: Spatial memory;    L-type voltage-dependent calcium channels;    Ryanodine receptors;    Neuroinflammation;    Calcium;   

Others  :  1228119
DOI  :  10.1186/s12974-015-0262-3

 received in 2014-12-29, accepted in 2015-02-09,  发布年份 2015

【 摘 要 】

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 28 days. 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.

【 授权许可】

   
2015 Hopp et al.; licensee BioMed Central.

【 图 表 】

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