GABAergic Remodeling and Astrocyte Dysfunction in Demyelination-Induced Neuronal Hyperexcitability

Epileptic seizures are diagnosed in patients with the autoimmune demyelinating disease multiple sclerosis (MS) at a rate three times higher than the population overall. Despite prognosticating fulminant course of disease and early mortality, scientific understanding of seizures in MS remains significantly limited. In this series of experiments, we observe electrographic, cellular, and molecular changes engendered by demyelinating disease that may feed into neuronal hyperexcitability and seizures using animal models and postmortem human brain tissue. We report that mice given 0.2% dietary Bis(cyclohexanone)oxaldihydrazone for up to twelve weeks display electrographic and behavioral seizures. Epileptiform discharges are observed in lateral cortical areas of these mice. In addition, differential changes to electroencephalogram spectral power in cortex and hippocampus in chronically demyelinated mice, suggesting regional heterogeneity in response. Electrographic changes occurred concomitant to GABAergic PV+ cell loss and remodeling of inhibitory synapses, upregulation of hippocampal glutamate receptors, and perturbation of molecules crucial for astrocyte metabolite handling. Loss of glutamate transporters and water channels were observed in postmortem human hippocampal tissue, bolstering the translational relevance of murine findings. These data suggest poorly constrained glutamatergic signaling pursuant to loss of parvalbumin+ GABAergic innervation, aberrant GluA2+ glutamate receptor expression, and altered astrocytic handling of potassium and glutamate may contribute to demyelination-induced seizures