title: Modeling of Age-Dependent Epileptogenesis by Differential Homeostatic Synaptic Scaling.
abstract: Homeostatic synaptic plasticity (HSP) has been implicated in the development of hyperexcitability and epileptic seizures following traumatic brain injury (TBI). Our in vivo experimental studies in cats revealed that the severity of TBI-mediated epileptogenesis depends on the age of the animal. To characterize mechanisms of these differences, we studied the properties of the TBI-induced epileptogenesis in a biophysically realistic cortical network model with dynamic ion concentrations. After deafferentation, which was induced by dissection of the afferent inputs, there was a reduction of the network activity and upregulation of excitatory connections leading to spontaneous spike-and-wave type seizures. When axonal sprouting was implemented, the seizure threshold increased in the model of young but not the older animals, which had slower or unidirectional homeostatic processes. Our study suggests that age-related changes in the HSP mechanisms are sufficient to explain the difference in the likelihood of seizure onset in young versus older animals. Significance statement: Traumatic brain injury (TBI) is one of the leading causes of intractable epilepsy. Likelihood of developing epilepsy and seizures following severe brain trauma has been shown to increase with age. Specific mechanisms of TBI-related epileptogenesis and how these mechanisms are affected by age remain to be understood. We test a hypothesis that the failure of homeostatic synaptic regulation, a slow negative feedback mechanism that maintains neural activity within a physiological range through activity-dependent modulation of synaptic strength, in older animals may augment TBI-induced epileptogenesis. Our results provide new insight into understanding this debilitating disorder and may lead to novel avenues for the development of effective treatments of TBI-induced epilepsy.
authors.affiliation: Graduate Neuroscience Program and Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521.
authors.forename: Oscar C
authors.initials: OC
authors.lastname: González
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521.
authors.forename: Giri P
authors.initials: GP
authors.lastname: Krishnan
authors.affiliation: Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, Quebec G1J 2G3, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chauvette
authors.affiliation: Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, Quebec G1J 2G3, Canada, Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Quebec G1V 0A6, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Timofeev
authors.affiliation: Salk Institute, La Jolla, California 92037, and Division of Biological Sciences, University of California, San Diego, California 92093.
authors.forename: Terrence
authors.initials: T
authors.lastname: Sejnowski
authors.affiliation: Graduate Neuroscience Program and Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, maksim.bazhenov@ucr.edu.
authors.forename: Maxim
authors.initials: M
authors.lastname: Bazhenov
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001369:Axons / Q000473:pathology; D001930:Brain Injuries / Q000150:complications* / Q000503:physiopathology; D002415:Cats; D003712:Dendrites / Q000473:pathology; D004827:Epilepsy / Q000209:etiology* / Q000503:physiopathology; D025461:Feedback, Physiological; D005260:Female; D006706:Homeostasis; D007395:Interneurons / Q000473:pathology; D007473:Ion Channels; D008297:Male; D008959:Models, Neurological; D009473:Neuronal Plasticity; D009475:Neurons, Afferent; D017966:Pyramidal Cells / Q000473:pathology; D012640:Seizures / Q000503:physiopathology; D013569:Synapses / Q000473:pathology*
chemical_list: D007473:Ion Channels
keywords: epileptic seizures; homeostatic plasticity; ion concentration dynamics; network models; synaptic plasticity