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

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. © 2015 hopp et al.