Abstract
In multiple sclerosis (MS), inflammation leads to damage of central nervous system myelin and axons. Previous studies have postulated impaired GABA transmission in MS, and recent postmortem analysis has shown that GABAergic parvalbumin (PV)-positive interneurons are decreased in the primary motor cortex (M1) of patients with MS. In this report, we present evidence for the loss of a specific population of GABAergic interneurons in the experimental autoimmune encephalomyelitis mouse model of MS. Using experimental autoimmune encephalomyelitis, we evaluated the distribution of both PV-positive interneurons and of the inhibitory presynaptic input in the M1 of experimental autoimmune encephalomyelitis and control mice. Our results demonstrate a specific decrease in the number of PV-positive interneurons in the M1 of mice with experimental autoimmune encephalomyelitis. We detected a significant reduction in the number of PV-positive interneurons in the layers II and III of the M1 of diseased mice, while there was no difference in the number of calretinin (CR)-positive cells between animals with experimental autoimmune encephalomyelitis and control animals. Moreover, we observed a significant reduction in the inhibitory presynaptic input in the M1 of treated mice. These changes were specific for the mice with elevated clinical score, while they were not detectable in the mice with low clinical score. Our results support the hypothesis that reinforcing the action of the GABAergic network may represent a therapeutic alternative to limit the progression of the neuronal damage in MS patients.
Highlights
Loss of neuronal function is an important pathological feature of multiple sclerosis (MS), and there is evidence for the contribution of neuronal damage toward clinical disability (Chard et al 2002)
We looked at the effects of experimental autoimmune encephalomyelitis (EAE) on the number and differentiation of PV-positive interneurons in the M1 of wild-type mice by comparing treated (EAE) and control animals, to establish whether we could reproduce the defect observed in the PV-positive cortical population of MS patients by using a well-established mouse model for EAE (Pluchino et al 2003)
With the findings in the human MS patients, we observed a specific negative effect of EAE on the PV-positive interneurons that appear to be more sensitive to the disease when compared to the CR-positive inhibitory interneurons
Summary
Loss of neuronal function is an important pathological feature of multiple sclerosis (MS), and there is evidence for the contribution of neuronal damage toward clinical disability (Chard et al 2002). Analysis on postmortem control and MS human brains has shown a reduction in the expression of a number of genes important in the neurotransmission by GABAergic inhibitory neurons in the motor cortex (M1) of MS patients (Dutta et al 2006). Defects in the expression of these calcium binding proteins have been implicated in a number of neurological pathologies including MS (Beers et al 2001; Eyels et al 2002). The data on postmortem MS brains have indicated a reduction in the expression of the PV gene as well as the reduced extension of neurites in PV-expressing interneurons within normal appearing gray matter in MS patients (Dutta et al 2006).
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