title: Focal epileptiform activity in the prefrontal cortex is associated with long-term attention and sociability deficits.
abstract: There is a well-described association between childhood epilepsy and pervasive cognitive and behavioral deficits. Often these children not only have ictal EEG events, but also frequent interictal abnormalities. The precise role of these interictal discharges in cognition remains unclear. In order to understand the relationship between frequent epileptiform discharges during neurodevelopment and cognition later in life, we developed a model of frequent focal interictal spikes (IIS). Postnatal day (p) 21 rats received injections of bicuculline methiodine into the prefrontal cortex (PFC). Injections were repeated in order to achieve 5 consecutive days of transient inhibitory/excitatory imbalance resulting in IIS. Short-term plasticity (STP) and behavioral outcomes were studied in adulthood. IIS is associated with a significant increase in STP bilaterally in the PFC. IIS rats did not show working memory deficits, but rather showed marked inattentiveness without significant alterations in motivation, anxiety or hyperactivity. Rats also demonstrated significant deficits in social behavior. We conclude that GABAergic blockade during early-life and resultant focal IIS in the PFC disrupt neural networks and are associated with long-term consequences for behavior at a time when IIS are no longer present, and thus may have important implications for ADHD and autism spectrum disorder associated with childhood epilepsy.
authors.affiliation: Department of Neurology, Program in Experimental and Molecular Medicine Dartmouth, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA 05405. Electronic address: Amanda.Hernan@uvm.edu.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Hernan
authors.affiliation: Department of Neurology, Program in Experimental and Molecular Medicine Dartmouth, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Alexander
authors.affiliation: Department of Neurology, Program in Experimental and Molecular Medicine Dartmouth, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Jenks
authors.affiliation: Department of Neurology, Program in Experimental and Molecular Medicine Dartmouth, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA 05405.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Barry
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA 05405.
authors.forename: Pierre-Pascal
authors.initials: PP
authors.lastname: Lenck-Santini
authors.affiliation: State Key Laboratory for Molecular and Cellular Biology, Kiev 01601, Ukraine; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA 05405.
authors.forename: Elena
authors.initials: E
authors.lastname: Isaeva
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA 05405.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Holmes
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA 05405; University College London, Institute of Child Health, London WC1N 1EH, UK. Electronic address: Rodney.Scott@med.uvm.edu.
authors.forename: Rod C
authors.initials: RC
authors.lastname: Scott
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001289:Attention Deficit Disorder with Hyperactivity / Q000209:etiology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000150:complications / Q000473:pathology*; D005106:Exploratory Behavior / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008570:Memory, Short-Term; D009042:Motivation; D009473:Neuronal Plasticity / Q000502:physiology; D017397:Prefrontal Cortex / Q000254:growth & development / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012920:Social Behavior Disorders / Q000209:etiology*; D013997:Time Factors
keywords: Attention; IIS; Interictal spikes; PFC; Pediatric epilepsy; Prefrontal cortex; STP; Short-term plasticity; Social behavior; interictal spike; prefrontal cortex; short term plasticity