Neuronal hyperexcitability and seizures are associated with changes in glial-neuronal interactions in the hippocampus of a mouse model of epilepsy with mental retardation |
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Authors: | Melø Torun Bigini Paolo Sonnewald Ursula Balosso Silvia Cagnotto Alfredo Barbera Sara Uboldi Sarah Vezzani Annamaria Mennini Tiziana |
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Institution: | Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. |
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Abstract: | Hippocampal excitability and the metabolic glial-neuronal interactions were investigated in 22-week-old mice with motor neuron degeneration (mnd), a model of progressive epilepsy with mental retardation. Mnd mice developed spontaneous spikes in the hippocampus and were more susceptible to kainate-induced seizures compared with control mice. Neuronal hyperexcitability in their hippocampus was confirmed by the selective increase of c-Fos positive nuclei. Glial activation and pro-inflammatory cytokines over-expression were observed in the hippocampus of mnd mice, even in the absence of marked hippocampal neurodegeneration, as suggested by unchanged amounts of neuroactive amino acids and N-acetyl aspartate. Concentration of other amino acids, including GABA and glutamate, was not changed as well. However, ex vivo(13) C magnetic resonance spectroscopy, after simultaneous injection of 1-(13) C]glucose and 1,2-(13) C]acetate, followed by decapitation, showed decreased 1,2-(13) C]GABA formation from hippocampal astrocytic precursors and a marked reduction in 4,5-(13) C]glutamate derived from glutamine. We suggest that astrocyte dysfunction plays a primary role in the pathology and that mnd mice are of value to investigate early pathogenetic mechanism of progressive epilepsy with mental retardation. |
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Keywords: | 13C nuclear magnetic resonance spectroscopy astrocytes and microglia glutamate and GABA hippocampus neuronal ceroid lipofuscinosis seizures |
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