Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

Nisticò, Robert; Mori, Francesco; Feligioni, Marco; Nicoletti, Ferdinando; Centonze, Diego

doi:10.1098/rstb.2013.0162

Cited by 45 publications

(44 citation statements)

References 68 publications

(123 reference statements)

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“…Results from clinical studies suggest that neuronal damage or neuronal loss critically contributes to functional deficits in MS patients. Of note, there is evidence that neuronal structures are not "simply" destroyed but in parallel neuronal plasticity is impaired in the CNS of MS patients (98). Virtually every element of the neuron can be damaged or even destroyed during gray matter demyelination including cell soma (82,108), dendritic spines (64), synapses (37,91,137) and neurites (108).…”

Section: What Triggers Neurodegeneration In Ms: Pathology Of the Nawmmentioning

confidence: 99%

“…Virtually every element of the neuron can be damaged or even destroyed during gray matter demyelination including cell soma (82,108), dendritic spines (64), synapses (37,91,137) and neurites (108). Of note, there is evidence that neuronal structures are not "simply" destroyed but in parallel neuronal plasticity is impaired in the CNS of MS patients (98).…”

Section: What Triggers Neurodegeneration In Ms: Pathology Of the Nawmmentioning

confidence: 99%

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Multiple sclerosis animal models: a clinical and histopathological perspective

et al. 2017

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There is a broad consensus that multiple sclerosis (MS) represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, that is, damage to axons, synapses and nerve cell bodies. While we are equipped with appropriate therapeutic options to prevent immune-cell driven relapses, effective therapeutic options to prevent the progressing neurodegeneration are still missing. In this review article, we will discuss to what extent pathology of the progressive disease stage can be modeled in MS animal models. While acute and relapsing-remitting forms of experimental autoimmune encephalomyelitis (EAE), which are T cell dependent, are aptly suited to model relapsing-remitting phases of MS, other EAE models, especially the secondary progressive EAE stage in Biozzi ABH mice is better representing the secondary progressive phase of MS, which is refractory to many immune therapies. Besides EAE, the cuprizone model is rapidly gaining popularity to study the formation and progression of demyelinating CNS lesions without T cell involvement. Here, we discuss these two non-popular MS models. It is our aim to point out the pathological hallmarks of MS, and discuss which pathological aspects of the disease can be best studied in the various animal models available.

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Section: What Triggers Neurodegeneration In Ms: Pathology Of the Nawmmentioning

confidence: 99%

Section: What Triggers Neurodegeneration In Ms: Pathology Of the Nawmmentioning

confidence: 99%

Multiple sclerosis animal models: a clinical and histopathological perspective

et al. 2017

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“…In support of this hypothesis, pharmacological blockade of glutamate receptors in rodent models of MS (experimental autoimmune encephalitis (EAE)), perturb disease progression and severity, reduce neurological deficits and decrease damage to axons and myelinating cells (oligodendrocytes), despite having no effect on CNS inflammation [151,152]. Furthermore, in acute brain slices from EAE models it has been shown that LTP is enhanced and LTD is reduced, leading to an overall hyperexcitable environment, similar to the human cortex [153][154][155].…”

Section: Multiple Sclerosismentioning

confidence: 99%

Synaptic pathology: A shared mechanism in neurological disease

Henstridge

Pickett

Spires‐Jones

2016

Ageing Research Reviews

135

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Synaptic proteomes have evolved a rich and complex diversity to allow the exquisite control of neuronal communication and information transfer. It is therefore not surprising that many neurological disorders are associated with alterations in synaptic function. As technology has advanced, our ability to study the anatomical and physiological function of synapses in greater detail has revealed a critical role for both central and peripheral synapses in neurodegenerative disease. Synapse loss has a devastating effect on cellular communication, leading to wide ranging effects such as network disruption within central neural systems and muscle wastage in the periphery. These devastating effects link synaptic pathology to a diverse range of neurological disorders, spanning Alzheimer's disease to multiple sclerosis. This review will highlight some of the current literature on synaptic integrity in animal models of disease and human post-mortem studies. Synaptic changes in normal brain ageing will also be discussed and finally the current and prospective treatments for neurodegenerative disorders will be summarised.

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“…A similar sequence of events may give rise to cognitive impairment in multiple sclerosis. Studies using the EAE rat model of multiple sclerosis show that release of IL-1β from infiltrating lymphocytes or activated microglia facilitates hippocampal long-term potentiation via inhibition of GABA-mediated synaptic activity and increased likelihood of glutamate-mediated excitotoxicity (Nisticó et al, 2013a(Nisticó et al, , 2013b. In contrast, Aβ inhibits induction of NMDA receptor-dependent long-term potentiation in hippocampal slices, and deficiency of iNOS or inhibitors of NADPH oxidase both relieved this inhibitory effect, implicating microglia-derived oxidants (Wang et al, 2004).…”

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confidence: 99%

Microglia antioxidant systems and redox signalling

Vilhardt¹,

Haslund-vinding

Jaquet³

et al. 2016

British J Pharmacology

109

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For many years, microglia, the resident CNS macrophages, have been considered only in the context of pathology, but microglia are also glial cells with important physiological functions. Microglia-derived oxidant production by NADPH oxidase (NOX2) is implicated in many CNS disorders. Oxidants do not stand alone, however, and are not always pernicious. We discuss in general terms, and where available in microglia, GSH synthesis and relation to cystine import and glutamate export, and the thioredoxin system as the most important antioxidative defence mechanism, and further, we discuss in the context of protein thiolation of target redox proteins the necessity for tightly localized, timed and confined oxidant production to work in concert with antioxidant proteins to promote redox signalling. NOX2-mediated redox signalling modulates the acquisition of the classical or alternative microglia activation phenotypes by regulating major transcriptional programs mediated through NF-κB and Nrf2, major regulators of the inflammatory and antioxidant response respectively. As both antioxidants and NOX-derived oxidants are co-secreted, in some instances redox signalling may extend to neighboring cells through modification of surface or cytosolic target proteins. We consider a role for microglia NOX-derived oxidants in paracrine modification of synaptic function through long term depression and in the communication with the adaptive immune system. There is little doubt that a continued foray into the functions of the antioxidant response in microglia will reveal antioxidant proteins as dynamic players in redox signalling, which in concert with NOX-derived oxidants fulfil important roles in the autocrine or paracrine regulation of essential enzymes or transcriptional programs. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations Aβ, amyloid-β peptide 1-42; DAMP, damage-associated molecular pattern molecules; GCL, glutamate cysteine ligase; GPx, GSH peroxidase; HNE, 4-hydroxy-2-nonenal; HO-1, haem oxygenase-1; KEAP1, Kelch-like ECH-associated protein; LTD, long-term depression; PLA 2 , phospholipase A 2 ; Prx, peroxiredoxins; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, cystine-glutamate exchanger IntroductionMicroglia, the resident immune cells of the brain, are exquisitely sensitive cells, which through a large and unique repertoire of sensing cell surface receptors (Hickman et al., 2013) responding to ligands of exogenous or endogenous nature (Kettenmann et al., 2013) continuously survey the brain parenchyma for even the smallest deviation from homeostasis. When the fine, motile processes of microglia encounter a problem, microglia assume an activation phenotype adapted to the quick resolution of damage and return to homeostasis. If instigating insults cannot be resolved, chronic microglia activation ensues. The differing nature of...

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Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

Cited by 45 publications

References 68 publications

Multiple sclerosis animal models: a clinical and histopathological perspective

Multiple sclerosis animal models: a clinical and histopathological perspective

Synaptic pathology: A shared mechanism in neurological disease

Microglia antioxidant systems and redox signalling

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