Impaired striatal GABA transmission in experimental autoimmune encephalomyelitis

Rossi, Silvia; Muzio, Luca; Chiara, Valentina De; Grasselli, Giorgio; Musella, Alessandra; Musumeci, Gabriele; Mandolesi, Georgia; Ceglia, Roberta De; Maida, Simona; Biffi, Emilia; Pedrocchi, Alessandra; Menegon, Andrea; Bernardi, Giorgio; Furlan, Roberto; Martino, Gianvito; Centonze, Diego

doi:10.1016/j.bbi.2010.10.004

Cited by 104 publications

(108 citation statements)

References 62 publications

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“…It is noteworthy that elevated IL-1b levels during focal inflammation in MS, as well as in the acute phase of EAE, can influence in opposite directions glutamatergic and GABAergic transmission (which is increased and inhibited by pro-inflammatory cytokines, respectively) [59,61,63,64]. Thus, neuroinflammation and IL-1b signalling network might contribute to the high prevalence of cognitive impairment associated with MS [67] and to the spatial learning deficits in EAE [62,66].…”

Section: Discussionmentioning

confidence: 99%

“…In all brain regions, synaptic dysfunctions involving either glutamatergic or GABAergic neurotransmission often precede the onset of motor deficits. In general, glutamatergic transmission seems to be enhanced in EAE, while GABAergic transmission is reduced [17,40,59,61,62]. Notably, these synaptic alterations are likely to occur also in the MS brain and have been associated with the activity of pro-inflammatory cytokines such as tumour necrosis factor-a (TNF-a) and IL-1b.…”

Section: Role Of Inflammatory Cytokinesmentioning

confidence: 99%

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Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

Nisticò

Mori

Feligioni

et al. 2014

Phil. Trans. R. Soc. B

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Approximately half of all patients with multiple sclerosis (MS) experience cognitive dysfunction, including learning and memory impairment. Recent studies suggest that hippocampal pathology is involved, although the mechanisms underlying these deficits remain poorly understood. Evidence obtained from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests that in the hippocampus of EAE mice long-term potentiation (LTP) is favoured over long-term depression in response to repetitive synaptic activation, through a mechanism dependent on enhanced IL-1β released from infiltrating lymphocytes or activated microglia. Facilitated LTP during an immune-mediated attack might underlie functional recovery, but also cognitive deficits and excitotoxic neurodegeneration. Having identified that pro-inflammatory cytokines such as IL-1β can influence synaptic function and integrity in early MS, it is hoped that new treatments targeted towards preventing synaptic pathology can be developed.

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Section: Discussionmentioning

confidence: 99%

Section: Role Of Inflammatory Cytokinesmentioning

confidence: 99%

Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

Nisticò

Mori

Feligioni

et al. 2014

Phil. Trans. R. Soc. B

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“…Of note, the striatum is emerging as a key structure in mood regulation in humans (20), and in rodents (2 I). In addition, this area is involved in MS (22), and in EAE (23 diminished spinal cord pathology relative to EAE mice receiving saline. The numbers of astrocytes, T cells, microglial/macrophages and damaged neurons were diminished, and the extent of demyelination was reduced in PEA-treated mice even when the treatment began after disease was observed.…”

Section: Effect Ofpea On Neuropathologymentioning

confidence: 99%

N-Palmitoylethanolamine Administration Ameliorates the Clinical Manifestation and Progression of Experimental Autoimmune Encephalomyelitis in Rodents

et al. 2014

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Experimental autoimmune encephalomyelitis in rodents (EAE) is an accepted in vivo model for immunopathogenic mechanisms underlying multiple sclerosis (MS) and tests possible treatment options because it mimics many of the disease patterns. The current treatments for delaying MS progression include cytostatic, immunomodulatory drugs such as mitoxantrone, cyclophosphamide (Cy), biological agents such as interferon (IFN)-beta, natalizumab and random polymer glatiramer acetate. Unfortunately, all of these compounds have potentially serious side effects, some require systemic administration, and the biological agents are costly and immunogenic, causing response failure during prolonged treatment. With this aim in mind, the purpose of the current research was to examine the effects of endogenous substances such as N-palmitoylethanolamine (PEA). PEA is an endogenous fatty acid amide belonging to the family of the N-acylethanolamines (NAEs). Recently, several studies demonstrated that PEA is an important analgesic, anti-inflammatory and neuroprotective mediator, acting at several molecular targets in both central and sensory nervous systems as well as immune cells. The effect of PEA daily administered was investigated in rats and mice developing EAE. A multidisciplinary approach was employed to study behavior and biochemical parameters. In our study we found that PEA counteracts the clinical course and pathology of monophasic EAE in myelin basic protein-immunized Lewis rats and the progression of EAE induced in C57BIA) mice by immunization with myelin oligodendrocyte glycoprotein. Our results show that PEA treatment had a beneficial effect on the two different EAE models.Multiple sclerosis (MS) is an autoimmune disease that affects approximately 400,000 people a year in the US, and more than 2.1 million people worldwide. Genetic, environmental and immunological factors have been linked with the etiology of this disease, but the cause or causes of MS are still unknown (I). Patients suffering from MS develop partial to complete paralysis as well as impaired cogmtrve function. While the exact trigger of MS remains unclear, it is known that the disease involves autoreactive T cells that infiltrate into the central nervous system (CNS) and target myelinated cells. Inflammation, demyelination and axonal damage in the CNS represent manifestation of MS (2).

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“…Patch-clamp technique in whole-cell configuration was performed on PCs to record sEPSC (as described in the electrophysiology method section and in in a solution composed by ACSF and CSF in ratio 1:1 at room temperature (Rossi et al, 2012a). To assess miR-142-3p electrophysiological effects, LNA anti-miR-142-3p was preincubated for 1 h with pooled miR-142-3p-high-level CSFs before performing electrophysiological recordings.…”

Section: Incubation Of Human Csf On Cerebellar Slices and Electrophysmentioning

confidence: 99%

“…Imbalance between glutamatergic and GABAergic transmission occurs in MS and in its animal model experimental autoimmune encephalomyelitis (EAE), representing a possible cause of excitotoxic damage (Sarchielli et al, 2003;Clements et al, 2008;Centonze et al, 2009;Bhat et al, 2010;Rossi et al, 2011, 2012b, Mandolesi et al, 2012Kostic et al, 2013;Azevedo et al, 2014;Ciccarelli et al, 2014; for review see Mandolesi et al, 2015). Inflammatory cytokines, released from infiltrating T cells and from activated microglia and astroglia, participate in such synaptic and neuronal alterations (Centonze et al, 2009;Mandolesi et al, 2012Mandolesi et al, , 2015Rossi et al, 2012a;Steinman, 2013;Mori et al, 2014), which are ongoing processes largely independent of axonal demyelination and transection. Because synaptic dysfunction and loss are reversible, targeting mechanisms that protect or repair synapses would enable clinical interventions at both early and late stages of MS (Mandolesi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

miR-142-3p Is a Key Regulator of IL-1β-Dependent Synaptopathy in Neuroinflammation

et al. 2017

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MicroRNAs (miRNA) play an important role in post-transcriptional gene regulation of several physiological and pathological processes. In multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the CNS, and in its mouse model, the experimental autoimmune encephalomyelitis (EAE), miRNA dysregulation has been mainly related to immune system dysfunction and white matter (WM) pathology. However, little is known about their role in gray matter pathology. Here, we explored miRNA involvement in the inflammation-driven alterations of synaptic structure and function, collectively known as synaptopathy, a neuropathological process contributing to excitotoxic neurodegeneration in MS/EAE. Particularly, we observed that miR-142-3p is increased in the CSF of patients with active MS and in EAE brains. We propose miR-142-3p as a molecular mediator of the IL-1␤-dependent downregulation of the glial glutamate-aspartate transporter (GLAST), which causes an enhancement of the glutamatergic transmission in the EAE cerebellum. The synaptic abnormalities mediated by IL-1␤ and the clinical and neuropathological manifestations of EAE disappeared in miR-142 knockout mice. Furthermore, we observed that in vivo miR-142-3p inhibition, either by a preventive and local treatment or by a therapeutic and systemic strategy, abolished IL-1␤-and GLAST-dependent synaptopathy in EAE wild-type mice. Consistently, miR-142-3p was responsible for the glutamatergic synaptic alterations caused by CSF of patients with MS, and CSF levels of miR-142-3p correlated with prospective MS disease progression. Our findings highlight miR-142-3p as key molecular player in IL-1␤-mediated synaptic dysfunction, possibly leading to excitotoxic damage in both EAE and MS diseases. Inhibition of miR-142-3p could be neuroprotective in MS.

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Impaired striatal GABA transmission in experimental autoimmune encephalomyelitis

Cited by 104 publications

References 62 publications

Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis

N-Palmitoylethanolamine Administration Ameliorates the Clinical Manifestation and Progression of Experimental Autoimmune Encephalomyelitis in Rodents

miR-142-3p Is a Key Regulator of IL-1β-Dependent Synaptopathy in Neuroinflammation

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