Deficient Glutamate Release in an Animal Model of Multiple Sclerosis

Buenos Aires

Simposio; Fronteras en BioCiencias. Simposio Conjunto de la Sociedad Max Planck y el Ministerio de Ciencia, Tecnología e Innovación Productiva.; 2012

Ministerio de Ciencia, Tecnología e Innovación Productiva

Multiple sclerosis (MS) is a human inflammatory demyelinating disease of the central nervous system that leads to motor, sensory, and cognitive deficits. Although it has been classically considered a white matter pathology, cortical lesions has increasingly received attention as they may contribute to disease progression and emergence of cognitive deficits. Experimental Autoimmune Encephalomyelitis (EAE) is a classical model that mimics many of the clinical and pathological features of MS. While EAE research has been mostly focused on spinal cord inflammation/demyelination, the extent of cortical alterations remains unclear. Herein we corroborate the previously found diminution in calcium-dependent glutamate release from frontal cortex synaptosomes of symptomatic EAE rats, showing that the total content of glutamate is not altered. Also, we found no changes in the percentage of glutamatergic or GABAergic terminals, as well as in the rise of cytosolic Ca²⁺ after depolarization. However, the decreased glutamate release was accompanied by changes in phosphorylation of Synapsin I and Erk 1/2. These alterations are reversed when the animals are completely recovered from the clinical signs of the disease. Together, these data indicate that the machinery of neurotransmitter release is affected in this animal model of MS, and shed light on the possible mechanisms of neuronal dysfunction in this disease. Our results show an inhibition in Ca2+-dependent neurotransmitter release in synaptosomes from frontal cortex of rats with EAE, which correlates with the beginning of the clinical signs and is reversed when the animals are recovered. Together, these data suggest an alteration in proteins of the machinery involved in neurotransmitter release rather than a deregulation in Ca2+ influx. Furthermore, this strongly supports the fact that cortical neuronal dysfunction could contribute to clinical symptoms and disease progression in EAE and, possibly, in MS.