Our results provide compelling evidence of the synaptic mechanism linking inflammation and excitotoxic neurodegeneration in MS.

Our results point to TNF as a primary neurotoxic molecule in progressive forms of MS.

Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-β(1-42) and τ protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-β(1-42) accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-β(1-42) is reduced in the CSF of these patients. In our sample of MS patients, amyloid-β(1-42) levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-β(1-42) levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with θ burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-β(1-42) CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between τ protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-β metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.

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Mood alterations are induced by intrathecal inflammation, even though not clinically apparent, and are able to predict inflammatory reactivations in RRMS. Inflammation is therefore a biological event, not less important than the traditional psychosocial factors, involved in mood disorders.

Neuroplasticity is essential to prevent clinical worsening despite continuing neuronal loss in several brain diseases, including multiple sclerosis (MS). The precise nature of the adaptation mechanisms taking place in MS brains, ensuring protection from disability appearance and accumulation, is however unknown. Here, we explored the hypothesis that long-term synaptic potentiation (LTP), potentially able to minimize the effects of neuronal loss by providing extra excitation of denervated neurons, is the most relevant form of adaptive plasticity in stable MS patients, and it is disrupted in progressing MS patients. We found that LTP, explored by means of transcranial magnetic theta burst stimulation over the primary motor cortex, was still possible, and even favored, in stable relapsing-remitting (RR-MS) patients, whereas it was absent in individuals with primary progressive MS (PP-MS). We also provided evidence that plateletderived growth factor (PDGF) plays a substantial role in favoring both LTP and brain reserve in MS patients, as this molecule: (1)

Interleukin-1␤ (IL-1␤) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-1␤-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-1␤-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-1␤ caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-1␤-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-1␤-CB1R coupling, and TRPV1Ϫ/Ϫ mice were indeed insensitive to the synaptic and behavioral effects of both IL-1␤ and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-1␤ on CB1Rs only in control mice, while the same treatment was ineffective in slices prepared from TRPV1Ϫ/Ϫ mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.

BACKGROUND AND PURPOSEAlterations of glutamate-mediated synaptic transmission occur early during neuroinflammatory insults, and lead to degenerative neuronal damage in multiple sclerosis (MS) and also in experimental autoimmune encephalomyelitis (EAE), which is a murine model of MS. Fingolimod is an effective orally active agent for the treatment of MS, affecting lymphocyte invasion of the brain. However, it is still unclear if fingolimod can be neuroprotective in this disorder. EXPERIMENTAL APPROACHUsing neurophysiological recordings and morphological evaluation of dendritic integrity, we evaluated the effects of oral fingolimod on the clinical score of EAE mice in order to determine whether the compound was associated with preservation of synaptic transmission. KEY RESULTSOral fingolimod prevented and reversed the pre-and postsynaptic alterations of glutamate transmission in EAE mice. These effects were associated with a clear amelioration of the clinical deterioration seen in EAE mice, and with a significant inhibition of neuronal dendritic pathology. Fingolimod did not alter the spontaneous excitatory postsynaptic currents in control animals, suggesting that only the pathological processes behind the inflammation-induced defects in glutamate transmission were modulated by this compound. CONCLUSIONS AND IMPLICATIONSThe beneficial effects of fingolimod on the clinical, synaptic and dendritic abnormalities of murine EAE might correlate with the neuroprotective actions of this agent, as observed in MS patients. LINKED ARTICLEThis article is commented on by Gillingwater, pp. 858-860 of this issue. To view this commentary visit http://dx.doi.org/ 10.1111/j. 1476-5381.2011.01612.x Abbreviations ACSF, artificial cerebrospinal fluid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; EAE, experimental autoimmune encephalomyelitis; EPSC, excitatory postsynaptic current; MS, multiple sclerosis; S1P, sphingosine-1-phosphate BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 British Journal of Pharmacology (2012) IntroductionThe clinical course of multiple sclerosis (MS) in most patients is characterized by recurrent inflammatory episodes in the early stages (relapsing-remitting MS), and by a progressive neurological decline in the late phases (secondary progressive MS). A minority of patients experience a progressive course of the disease demonstrable immediately after the onset of the disease (primary progressive MS) (Compston and Coles, 2008;Trapp and Nave, 2008). Inflammation-triggered neurodegenerative damage is ultimately responsible for the primary and secondary progressive phases of MS, and this damage is particularly refractory to currently approved immunomodulatory or immunosuppressant therapies (Amor et al., 2010;Dutta and Trapp, 2010;Bates, 2011).Fingolimod is an effective orally active agent for the treatment of MS, which is able to interfere with the inflammatory phase of the disease through the prevention of lymphocyte invasion of the CNS (Matloubian et al., 2004;Kataoka et al., ...