title: Prostaglandin E2-induced synaptic plasticity in neocortical networks of organotypic slice cultures.
abstract: Traumatic brain injury (TBI) is a major cause of epilepsy, yet the mechanisms underlying the progression from TBI to epilepsy are unknown. TBI induces the expression of COX-2 (cyclooxygenase-2) and increases levels of prostaglandin E2 (PGE2). Here, we demonstrate that acutely applied PGE2 (2 mum) decreases neocortical network activity by postsynaptically reducing excitatory synaptic transmission in acute and organotypic neocortical slices of mice. In contrast, long-term exposure to PGE2 (2 mum; 48 h) presynaptically increases excitatory synaptic transmission, leading to a hyperexcitable network state that is characterized by the generation of paroxysmal depolarization shifts (PDSs). PDSs were also evoked as a result of depriving organotypic slices of activity by treating them with tetrodotoxin (TTX, 1 mum; 48 h). This treatment predominantly increased postsynaptically excitatory synaptic transmission. The network and cellular effects of PGE2 and TTX treatments reversed within 1 week. Differences in the underlying mechanisms (presynaptic vs postsynaptic) as well as occlusion experiments in which slices were exposed to TTX plus PGE2 suggest that the two substances evoke distinct forms of homeostatic plasticity, both of which result in a hyperexcitable network state. PGE2 and TTX (alone or together with PGE2) also increased levels of apoptotic cell death in organotypic slices. Thus, we hypothesize that the increase in excitability and apoptosis may constitute the first steps in a cascade of events that eventually lead to epileptogenesis triggered by TBI.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101, USA. henner.koch@seattlechildrens.org
authors.forename: Henner
authors.initials: H
authors.lastname: Koch
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Huh
authors.forename: Frank P
authors.initials: FP
authors.lastname: Elsen
authors.forename: Michael S
authors.initials: MS
authors.lastname: Carroll
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Hodge
authors.forename: Francesco
authors.initials: F
authors.lastname: Bedogni
authors.forename: Michael S
authors.initials: MS
authors.lastname: Turner
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hevner
authors.forename: Jan-Marino
authors.initials: JM
authors.lastname: Ramirez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D015232:Dinoprostone
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