Interleukin-1  Alters Glutamate Transmission at Purkinje Cell Synapses in a Mouse Model of Multiple Sclerosis

Mandolesi, Georgia; Musella, Alessandra; Gentile, Antonietta; Grasselli, Giorgio; Haji, Nabila; Sepman, Helena; Fresegna, Diego; Bullitta, Silvia; Vito, Francesca De; Musumeci, Gabriele; Sanza, Claudio Di; Strata, Piergiorgio; Centonze, Diego

doi:10.1523/jneurosci.5369-12.2013

Cited by 131 publications

(134 citation statements)

References 91 publications

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“…TLR4 activation triggers a cascade of signaling events leading to the release of many proinflammatory cytokines. These cytokines, such as tumor necrosis factor-a and interleukin-1b, not only exert their excitatory effects via upregulating excitatory synaptic transmission [30,31], but also regulate neuronal functions via interacting with modulatory systems [32]. All these TLR4-mediated molecular and cellular consequences are pivotal to relevant neuropsychiatric diseases.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Yan

Cheng

et al. 2016

Neurosci. Bull.

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Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4 -/-) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4 -/-mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4 -/-mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4 -/-mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4 -/-mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4 -/-mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon.

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Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Yan

Cheng

et al. 2016

Neurosci. Bull.

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“…In conclusion, the role of miR-142-3p in the detrimental regulation of the synaptic response to inflammation and in MS disease progression opens new avenues in our understanding of MS pathophysiology, with potentially relevant implications for therapeutic strategies based on an anti-miRNA approach (Li and Rana, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…EAE was induced in 6-to 8-week-old mice by active immunization with an emulsion of myelin oligodendrocyte glycoprotein peptide ) in Complete Freund's Adjuvant (CFA), followed by intravenous administration of pertussis toxin (500 ng) on the day of immunization and 2 d later (Centonze et al, 2009;Mandolesi et al, 2012. Control animals received the same treatment as EAE mice without the immunogen MOG peptide (referred to as hereafter as "CFA").…”

Section: Methodsmentioning

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%

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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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“…Unfortunately, the pathophysiology of the cerebellar symptoms in MS is complex and only partially understood. Cerebellar deficits have been associated not only with demyelination and cerebellar atrophy caused by Purkinje cell death but also with severe synaptic dysfunctions, indicating a prominent role for gray matter pathology in both MS and EAE [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Il-1β Dependent Cerebellar Synaptopathy in a Mouse Mode of Multiple Sclerosis

et al. 2014

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Multiple sclerosis (MS) is considered as an autoimmune inflammatory disease and is one of the main causes of motor disability in young adults. Focal white matter lesions consisting of T lymphocyte and macrophage infiltrates, demyelination, and axonal transection are clear hallmarks of MS disease. However, white matter pathology does not occur exclusively. Clinical and experimental studies have shown gray matter atrophy and lesions occurring in several brain regions, including the cerebellum. Cerebellar-dependent disability is very common in MS patients. Cerebellar deficits are also relatively refractory to symptomatic therapy and progress even under disease-modifying agents. However, the neuropathology underlying cerebellar dysfunction remains largely unknown. We recently demonstrated that the cerebellum is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. Electrophysiological studies, supported by immunofluorescence and biochemical analysis, revealed an imbalance between the spontaneous excitatory and inhibitory synaptic transmission at Purkinje cell synapses. While the frequency of the spontaneous inhibitory postsynaptic currents (sIPSC) during the acute phase of EAE was reduced in correlation with a selective degeneration of basket and stellate neurons, the glutamatergic transmission was enhanced due to a reduced expression and functioning of glutamate aspartate transporter (GLAST)/excitatory amino acid transporter 1 (EAAT1), the most abundant glutamate transporter expressed by Bergmann glia. Of note, we demonstrated that the proinflammatory cytokine interleukin-1β (IL-1β), highly expressed in EAE cerebellum and released by infiltrating lymphocytes, was one of the molecular players directly responsible for such synaptic alterations during the acute phase. Furthermore, other brain regions in EAE mice seem to be affected by a similar inflammatory dependent synaptopathy, suggesting common molecular targets for potential therapeutic strategies. Accordingly, we observed that intracerebroventricular inhibition of IL-1β signaling in EAE mice was able to ameliorate inflammatory reaction, electrophysiological response, and clinical disability, indicating a pivotal role of IL-1β in EAE disease and likely, in MS.

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Interleukin-1 Alters Glutamate Transmission at Purkinje Cell Synapses in a Mouse Model of Multiple Sclerosis

Cited by 131 publications

References 91 publications

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

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

Il-1β Dependent Cerebellar Synaptopathy in a Mouse Mode of Multiple Sclerosis

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