Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

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

Authors: Sarah C Hopp, Heather M D’Angelo, Sarah E Royer, Roxanne M Kaercher, Alexis M Crockett, Linda Adzovic, Gary L Wenk

Published in: Journal of Neuroinflammation | Issue 1/2015

Login to get access

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.
Literature
1.
2.
Hanisch U-K, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:1387–94.CrossRefPubMed
3.
Hauss-Wegrzyniak B, Dobrzanski P, Stoehr JD, Wenk GL. Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease. Brain Res. 1998;780:294–303.CrossRefPubMed
4.
Hauss-Wegrzyniak B, Vannucchi MG, Wenk GL. Behavioral and ultrastructural changes induced by chronic neuroinflammation in young rats. Brain Res. 2000;859:157–66.CrossRefPubMed
5.
Hauss-Wegrzyniak B, Vraniak PD, Wenk GL. LPS-induced neuroinflammatory effects do not recover with time. NeuroRep. 2000;11:1759–63.CrossRef
6.
Hauss-Wegrzyniak B, Lynch MA, Vraniak PD, Wenk GL. Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses. Exp Neurol. 2002;176:336–41.CrossRefPubMed
7.
Etcheberrigaray R, Hirashima N, Nee L, Prince J, Govoni S, Racchi M, et al. Calcium responses in fibroblasts from asymptomatic members of Alzheimer’s disease families. Neurobiol Dis. 1998;5:37–45.CrossRefPubMed
8.
Anekonda TS, Quinn JF. Calcium channel blocking as a therapeutic strategy for Alzheimer’s disease: the case for isradipine. Biochim Biophys Acta. 1812;2011:1584–90.
9.
Tollefson GD. Short-term effects of the calcium channel blocker nimodipine (Bay-e-9736) in the management of primary degenerative dementia. Biol Psychiat. 1990;27:1133–42.CrossRefPubMed
10.
Bruno AM, Huang JY, Bennett DA, Marr RA, Hastings ML, Stutzmann GE. Altered ryanodine receptor expression in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2012;33:1001–6.CrossRefPubMedCentralPubMed
11.
Koran MEI, Hohman TJ, Thornton-Wells TA. Genetic interactions found between calcium channel genes modulate amyloid load measured by positron emission tomography. Human Gen. 2014;133:85–93.CrossRef
12.
Hashioka S, Klegeris A, McGeer PL. Inhibition of human astrocyte and microglia neurotoxicity by Ca+2 channel blockers. Neuropharmacol. 2012;63:685–91.CrossRef
13.
Li Y, Hu X, Liu Y, Bao Y, An L. Nimodipine protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. Neuropharmacol. 2009;56:580–9.CrossRef
14.
Klegeris A, Choi HB, McLarnon JG, McGeer PL. Functional ryanodine receptors are expressed by human microglia and THP-1 cells: their possible involvement in modulation of neurotoxicity. J Neurosci Res. 2007;85:2207–15.CrossRefPubMed
15.
McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging. 2007;28:639–47.CrossRefPubMed
16.
Sitcheran R, Gupta P, Fisher PB, Baldwin AS. Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression. EMBO J. 2005;24:510–20.CrossRefPubMedCentralPubMed
17.
Takaki J, Fujimori K, Miura M, Suzuki T, Sekino Y, Sato K. L-glutamate released from activated microglia downregulates astrocytic L-glutamate transporter expression in neuroinflammation: the “collusion” hypothesis for increased extracellular L-glutamate concentration in neuroinflammation. J Neuroinflam. 2012;9:275–82.CrossRef
18.
Prow NA, Irani DN. The inflammatory cytokine, interleukin-1 beta, mediates loss of astroglial glutamate transport and drives excitotoxic motor neuron injury in the spinal cord during acute viral encephalomyelitis. J Neurochem. 2008;105:1276–86.CrossRefPubMedCentralPubMed
19.
Wu S-Z, Bodles A, Porter M, Griffin WS, Basile A, Barger S. Induction of serine racemase expression and D-serine release from microglia by amyloid beta-peptide. J Neuroinflam. 2004;2004(1):2–9.CrossRef
20.
Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, et al. Interleukin-1beta enhances NMDA receptor-mediated intracellular Ca+2 increase through activation of the Src family of kinases. J Neurosci. 2003;23:8692–700.PubMed
21.
Orellana DI, Quintanilla RA, Gonzalez-Billault C, Maccioni RB. Role of the JAKs/STATs pathway in the intracellular Ca+2 changes induced by interleukin-6 in hippocampal neurons. Neurotox Res. 2005;8:295–304.CrossRefPubMed
22.
Furukawa K, Mattson MP. The transcription factor NF-kappaB mediates increases in Ca+2 currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. J Neurochem. 1998;70:1876–86.CrossRefPubMed
23.
Friedrich O, Yi B, Edwards JN, Reischl B, Wirth-Hücking A, Buttgereit A. Interleukin-1α reversibly inhibits skeletal muscle ryanodine receptor: a novel mechanism for critical illness myopathy? Am J Respir Cell Mol Biol. 2014;50:1096–106.CrossRefPubMed
24.
Palmi M, Meini A. Role of the nitric oxide/cyclic GMP/Ca2+ signaling pathway in the pyrogenic effect of interleukin-1beta. Molec Neurobiol. 2002;25:133–47.CrossRef
25.
Min SS, Quan HY, Ma J, Han J-S, Jeon BH, Seol GH. Chronic brain inflammation impairs two forms of long-term potentiation in the rat hippocampal CA1 area. Neurosci Lett. 2009;456:20–4.CrossRefPubMed
26.
Segal M, Manor D. Confocal microscopic imaging of [Ca2+]i in cultured rat hippocampal neurons following exposure to N-methyl-D-aspartate. J Physiol. 1992;448:655–76.CrossRefPubMedCentralPubMed
27.
Lei SZ, Zhang D, Abele AE, Lipton SA. Blockade of NMDA receptor-mediated mobilization of intracellular Ca2+ prevents neurotoxicity. Brain Res. 1992;598:196–202.CrossRefPubMed
28.
Foster TC. Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity. Prog Neurobiol. 2012;96:283–303.CrossRefPubMedCentralPubMed
29.
Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, et al. Arg31/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation. J Neurosci. 2001;21:5484–93.PubMed
30.
Brothers HM, Bardou I, Hopp SC, Kaercher RM, Corona AW, Fenn AM, et al. Riluzole partially rescues age-associated, but not LPS-induced, loss of glutamate transporters and spatial memory. J Neuroimmune Pharmacol. 2013;8:1098–105.CrossRefPubMed
31.
Bardou I, Brothers HM, Kaercher RM, Hopp SC, Wenk GL. Differential effects of duration and age on the consequences of neuroinflammation in the hippocampus. Neurobiol Aging. 2013;34:2293–30.CrossRefPubMedCentralPubMed
32.
Rosi S, Vazdarjanova A, Ramirez-Amaya V, Worley PF, Barnes CA, Wenk GL. Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neurosci. 2006;142:1303–15.CrossRef
33.
Hopp SC, D’Angelo HM, Royer SE, Kaercher RM, Crockett AM, Adzovic L, et al. Spatial memory deficits in aged rats correlate with markers of calcium dysregulation: differential rescue by L-VDCC and RyR antagonism. Neurosci. 2014;240:10–8.CrossRef
34.
Thibault O, Landfield PW. Increase in single L-type Ca+2 channels in hippocampal neurons during aging. Science. 1996;272:1017–20.CrossRefPubMed
35.
Kumar A, Foster TC. Enhanced long-term potentiation during aging is masked by processes involving intracellular calcium stores. J Neurophysiol. 2004;91:2437–44.CrossRefPubMed
36.
Bodhinathan K, Kumar A, Foster TC. Redox sensitive calcium stores underlie enhanced after hyperpolarization of aged neurons: role for ryanodine receptor mediated calcium signaling. J Neurophysiol. 2010;104:2586–93.CrossRefPubMedCentralPubMed
37.
Disterhoft JF, Thompson LT, Moyer JR, Mogul DJ. Ca+2-dependent afterhyperpolarization and learning in young and aging hippocampus. Life Sci. 1996;59:413–20.CrossRefPubMed
38.
Sama DM, Mohmmad Abdul H, Furman JL, Artiushin IA, Szymkowski DE, Scheff SW, et al. Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats. PLoS One. 2012;7:e38170.CrossRefPubMedCentralPubMed
39.
Borde M, Bonansco C. Fernández de Sevilla D, Le Ray D, Buño W. Voltage-clamp analysis of the potentiation of the slow Ca2 + −activated K+ current in hippocampal pyramidal neurons. Hippocampus. 2000;10:198–206.CrossRefPubMed
40.
Clodfelter GV, Porter NM, Landfield PW, Thibault O. Sustained Ca2 + −induced Ca2 + −release underlies the post-glutamate lethal Ca2+ plateau in older cultured hippocampal neurons. Eur J Pharmacol. 2002;447:189–200.CrossRefPubMed
41.
Chavis P, Fagni L, Lansman JB, Bockaert J. Functional coupling between ryanodine receptors and L-type calcium channels in neurons. Nature. 1996;382:719–22.CrossRefPubMed
42.
Wenk GL, Parsons CG, Danysz W. Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine. Behav Pharmacol. 2006;17:411–24.CrossRefPubMed
43.
Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, et al. Inhibition of activity-dependent Arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci. 2000;20:3993–4001.PubMed
44.
Chawla MK, Guzowski JF, Ramirez-Amaya V, Lipa P, Hoffman KL, Marriott LK, et al. Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentata by brief spatial experience. Hippocampus. 2005;15:579–86.CrossRefPubMed
45.
Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, et al. Arc/Arg31 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron. 2006;52:445–59.CrossRefPubMedCentralPubMed
46.
Rial Verde EM, Lee-Osbourne J, Worley PF, Malinow R, Cline HT. Increased expression of the immediate-early gene Arc/arg31 reduces AMPA receptor-mediated synaptic transmission. Neuron. 2006;52:461–74.CrossRefPubMedCentralPubMed
47.
Waung MW, Pfeiffer BE, Nosyreva ED, Ronesi JA, Huber KM. Rapid translation of Arc/Arg31 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron. 2008;59:84–97.CrossRefPubMedCentralPubMed
48.
Shepherd JD, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D, et al. Arc/Arg31 mediates homeostatic synaptic scaling of AMPA receptors. Neuron. 2006;52:475–84.CrossRefPubMedCentralPubMed
49.
Wiegert JS, Oertner TG. Long-term depression triggers the selective elimination of weakly integrated synapses. Proc Natl Acad Sci U S A. 2013;110:E4510–9.CrossRefPubMedCentralPubMed
50.
Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, et al. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem. 2006;281:21362–8.CrossRefPubMed
51.
Santello M, Bezzi P, Volterra A. TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron. 2011;69:988–1001.CrossRefPubMed
52.
Simões AP, Duarte JA, Agasse F, Canas PM, Tomé AR, Agostinho P, et al. Blockade of adenosine A(2A) receptors prevents interleukin-1β-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway. J Neuroinflam. 2012;9:204–9.CrossRef
53.
Mattsson P, Aldskogius H, Svensson M. Nimodipine-induced improved survival rate of facial motor neurons following intracranial transection of the facial nerve in the adult rat. J Neurosurg. 1999;90:760–5.CrossRefPubMed
54.
Yanpallewar SU, Hota D, Rai S, Kumar M, Acharya SB. Nimodipine attenuates biochemical, behavioral and histopathological alterations induced by acute transient and long-term bilateral common carotid occlusion in rats. Pharmacol Res. 2004;49:143–50.CrossRefPubMed
55.
Chen X, Wu J, Lvovskaya S, Herndon E, Supnet C, Bezprozvanny I. Dantrolene is neuroprotective in Huntington’s disease transgenic mouse model. Mol Neurodegen. 2011;6:81–9.CrossRef
56.
Oulès B, Del Prete D, Greco B, Zhan X, Lauritzen I, Sevalle J, et al. Ryanodine receptor blockade reduces amyloid-β load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci. 2012;32:11820–34.CrossRefPubMedCentralPubMed
57.
Peng J, Liang G, Inan S, Wu Z, Joseph DJ, Meng Q, et al. Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett. 2012;516:274–9.CrossRefPubMedCentralPubMed
58.
Chen X, Tang T-S, Tu H, Nelson O, Pook M, Hammer R, et al. Deranged Ca+2 signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci. 2008;28:12713–24.CrossRefPubMedCentralPubMed
59.
60.
61.
Evert BO, Schelhaas J, Fleischer H, De Vos RAI, Brunt ER, Stenzel W, et al. Neuronal intranuclear inclusions, dysregulation of cytokine expression and cell death in spinocerebellar ataxia type 3. Clin Neuropathol. 2006;25:272–81.PubMed
62.
Hoffmann A, Kann O, Ohlemeyer C, Hanisch U-K, Kettenmann H. Elevation of basal intracellular Ca+2 as a central element in the activation of brain macrophages (microglia): suppression of receptor-evoked Ca+2 signaling and control of release function. J Neurosci. 2003;23:4410–9.PubMed
63.
Colton CA, Jia M, Li MX, Gilbert DL. K+ modulation of microglial superoxide production: involvement of voltage-gated Ca2+ channels. Am J Physiol. 1994;266:C1650–5.PubMed
64.
65.
Quan N, Sundar SK, Weiss JM. Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide. J Neuroimmunol. 1994;49:125–34.CrossRefPubMed
66.
Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–8.CrossRefPubMed
67.
Kettenmann H, Hoppe D, Gottmann K, Banati R, Kreutzberg G. Cultured microglial cells have a distinct pattern of membrane channels different from peritoneal macrophages. J Neurosci Res. 1990;26:278–87.CrossRefPubMed
68.
De Jong EK, Dijkstra IM, Hensens M, Brouwer N, Van Amerongen M, Liem RSB, et al. Vesicle-mediated transport and release of CCL21 in endangered neurons: a possible explanation for microglia activation remote from a primary lesion. J Neurosci. 2005;25:7548–57.CrossRefPubMed
Metadata
Title
Calcium dysregulation via L-type voltage-dependent calcium channels and ryanodine receptors underlies memory deficits and synaptic dysfunction during chronic neuroinflammation
Authors
Sarah C Hopp
Heather M D’Angelo
Sarah E Royer
Roxanne M Kaercher
Alexis M Crockett
Linda Adzovic
Gary L Wenk
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0262-3

Other articles of this Issue 1/2015

Journal of Neuroinflammation 1/2015 Go to the issue

Research

Antagonist of the neurokinin-1 receptor curbs neuroinflammation in ex vivo and in vitro models of Lyme neuroborreliosis

Research

Progesterone treatment reduces neuroinflammation, oxidative stress and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury

Review

Mapping neuroinflammation in frontotemporal dementia with molecular PET imaging

Research

Prolonged diet-induced obesity in mice modifies the inflammatory response and leads to worse outcome after stroke

Retraction Note

Retraction Note: Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/CX3CR1 signaling

Review

Mast cells in meningiomas and brain inflammation