Interleukin-1ß causes synaptic hyperexcitability in multiple sclerosis.
Ann Neurol
; 71(1): 76-83, 2012 Jan.
Article
em En
| MEDLINE
| ID: mdl-22275254
ABSTRACT
OBJECTIVE:
The frequency of inflammatory episodes in the early stages of multiple sclerosis (MS) has been correlated with late neurodegeneration, but the mechanism by which inflammation gives rise to delayed neuronal damage is unknown. Increased activity of the neurotransmitter glutamate is thought to play a role in the inflammation-driven neurodegenerative process of MS, and therefore we tested whether inflammatory cytokines released during acute MS attacks have the property of enhancing glutamate-mediated transmission and excitotoxicity in central neurons.METHODS:
We compared the effect of cerebrospinal fluid (CSF) from active and quiescent MS patients on glutamate-mediated excitatory postsynaptic currents (EPSCs) and excitotoxic damage in rodent brain slices. We also measured CSF concentrations of tumor necrosis factor-α, of interleukin-1ß (IL-1ß), and of IL-1 receptor antagonist (IL-1ra), and correlated cytokine levels with cortical excitability assessed in MS patients by means of paired-pulse transcranial magnetic stimulation (TMS).RESULTS:
CSF from MS patients with enhanced brain lesions at magnetic resonance imaging was able to increase spontaneous EPSC frequency and glutamate-mediated neuronal swelling in vitro, through a mechanism dependent on enhanced IL-1ß signaling and increased glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor stimulation. Furthermore, IL-1ß/IL-1ra ratio was significantly higher in the CSF of active MS subjects, and correlated with intracortical facilitation, an accredited TMS measure of glutamate transmission. Finally, we identified for the first time transient receptor potential vanilloid 1 channels as essential intermediates for the synaptic action of IL-1ß on central glutamatergic synapses.INTERPRETATION:
Our results provide compelling evidence of the synaptic mechanism linking inflammation and excitotoxic neurodegeneration in MS.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transmissão Sináptica
/
Potenciais Pós-Sinápticos Excitadores
/
Interleucina-1beta
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Esclerose Múltipla
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Adult
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Ann Neurol
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Itália