Age-Dependent Reduction in the Expression Levels of Genes Involved in Progressive Myoclonus Epilepsy Correlates with Increased Neuroinflammation and Seizure Susceptibility in Mouse Models.

Brain aging is characterized by a gradual decline in cellular homeostatic processes, thereby losing the ability to respond to physiological stress. At the anatomical level, the aged brain is characterized by degenerating neurons, proteinaceous plaques and tangles, intracellular deposition of glycogen, and elevated neuroinflammation. Intriguingly, such age-associated changes are also seen in neurodegenerative disorders suggesting that an accelerated aging process could be one of the contributory factors for the disease phenotype. Amongst these, the genetic forms of progressive myoclonus epilepsy (PME), resulting from loss-of-function mutations in genes, manifest symptoms that are common to age-associated disorders, and genes mutated in PME are involved in the cellular homeostatic processes. Intriguingly, the incidence and/or onset of epileptic seizures are known to increase with age, suggesting that physiological changes in the aged brain might contribute to increased susceptibility to seizures. We, therefore, hypothesized that the expression level of genes implicated in PME might decrease with age, thereby leading to a compromised neuronal response towards physiological stress and hence neuroinflammation in the aging brain. Using mice models, we demonstrate here that the expression level of PME genes shows an inverse correlation with age, neuroinflammation, and compromised heat shock response. We further show that the pharmacological suppression of neuroinflammation ameliorates seizure susceptibility in aged animals as well as in animal models for a PME. Taken together, our results indicate a functional role for the PME genes in normal brain aging and that neuroinflammation could be a major contributory player in susceptibility to seizures.