BACKGROUND AND PURPOSE: Increasing evidence shows the dysregulation of glutamate transmission in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A clear hallmark of EAE is an increased glutamate transmission associated with the up-regulation of AMPA receptors. However, little is known about the role of NMDA receptors (NMDAR) in the synaptic modifications induced by EAE. EXPERIMENTAL APPROACH: The contribution of NMDARs in the alterations of glutamate transmission and disease severity in EAE mice was assessed by means of neurophysiological, morphological, western blot, metabolic and clinical score evaluations. KEY RESULTS: Our results showed the appearance in EAE of an NMDAR-dependent increase of glutamate release, associated with dramatic activation of the astroglia. Presynaptic NMDARs became overactive during EAE, playing a positive role in modulating synaptic glutamate release in a way dependent on voltage-gated sodium channels. By means of NAD(P)H autofluorescence analysis, we also found that EAE has a glutamate and NMDAR-dependent dysfunction of mitochondrial activity, which is known to contribute to the neurodegenerative damage of MS and EAE. Furthermore, pharmacological blockade of NMDARs in vivo resulted in an amelioration of both synaptic transmission defects and of the clinical disease course of EAE mice, while EAE induced in mice with a genetically enhanced NMDAR signaling had opposite effects. CONCLUSIONS AND IMPLICATIONS: Our data, showing both sensitization of NMDARs and their involvement in the progression of the EAE disease, support pharmacological impairment of NMDAR signalling as a candidate to neuroprotection strategy in MS. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

MUSELLA, ALESSANDRA;Mandolesi G;
2012

Abstract

BACKGROUND AND PURPOSE: Increasing evidence shows the dysregulation of glutamate transmission in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A clear hallmark of EAE is an increased glutamate transmission associated with the up-regulation of AMPA receptors. However, little is known about the role of NMDA receptors (NMDAR) in the synaptic modifications induced by EAE. EXPERIMENTAL APPROACH: The contribution of NMDARs in the alterations of glutamate transmission and disease severity in EAE mice was assessed by means of neurophysiological, morphological, western blot, metabolic and clinical score evaluations. KEY RESULTS: Our results showed the appearance in EAE of an NMDAR-dependent increase of glutamate release, associated with dramatic activation of the astroglia. Presynaptic NMDARs became overactive during EAE, playing a positive role in modulating synaptic glutamate release in a way dependent on voltage-gated sodium channels. By means of NAD(P)H autofluorescence analysis, we also found that EAE has a glutamate and NMDAR-dependent dysfunction of mitochondrial activity, which is known to contribute to the neurodegenerative damage of MS and EAE. Furthermore, pharmacological blockade of NMDARs in vivo resulted in an amelioration of both synaptic transmission defects and of the clinical disease course of EAE mice, while EAE induced in mice with a genetically enhanced NMDAR signaling had opposite effects. CONCLUSIONS AND IMPLICATIONS: Our data, showing both sensitization of NMDARs and their involvement in the progression of the EAE disease, support pharmacological impairment of NMDAR signalling as a candidate to neuroprotection strategy in MS. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.12078/309
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