title: Calcium dysregulation via L-type voltage-dependent calcium channels and ryanodine receptors underlies memory deficits and synaptic dysfunction during chronic neuroinflammation.
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 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.
authors.affiliation: Departments of Neuroscience, Ohio State University, Columbus, OH, 43210, USA. hopp.8@osu.edu.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Hopp
authors.affiliation: Department of Psychology, Ohio State University, 1835 Neil Ave, Columbus, OH, 43210, USA. dangelo.42@osu.edu.
authors.forename: Heather M
authors.initials: HM
authors.lastname: D'Angelo
authors.affiliation: Departments of Neuroscience, Ohio State University, Columbus, OH, 43210, USA. royer.49@osu.edu.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Royer
authors.affiliation: Department of Psychology, Ohio State University, 1835 Neil Ave, Columbus, OH, 43210, USA. Kaercher.7@osu.edu.
authors.forename: Roxanne M
authors.initials: RM
authors.lastname: Kaercher
authors.affiliation: Departments of Neuroscience, Ohio State University, Columbus, OH, 43210, USA. crockett.111@osu.edu.|Department of Psychology, Ohio State University, 1835 Neil Ave, Columbus, OH, 43210, USA. crockett.111@osu.edu.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Crockett
authors.affiliation: Department of Psychology, Ohio State University, 1835 Neil Ave, Columbus, OH, 43210, USA. Adzovic.1@osu.edu.
authors.forename: Linda
authors.initials: L
authors.lastname: Adzovic
authors.affiliation: Departments of Neuroscience, Ohio State University, Columbus, OH, 43210, USA. wenk.6@osu.edu.|Department of Psychology, Ohio State University, 1835 Neil Ave, Columbus, OH, 43210, USA. wenk.6@osu.edu.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Wenk
mesh_terms: D000386:AIDS-Related Complex / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D003620:Dantrolene / Q000627:therapeutic use; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology*; D009125:Muscle Relaxants, Central / Q000627:therapeutic use; D009553:Nimodipine / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D065852:Spatial Memory / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D008070:Lipopolysaccharides; D009125:Muscle Relaxants, Central; D019837:Ryanodine Receptor Calcium Release Channel; D009553:Nimodipine; D003620:Dantrolene; D002118:Calcium