title: Enduring Memory Impairments Provoked by Developmental Febrile Seizures Are Mediated by Functional and Structural Effects of Neuronal Restrictive Silencing Factor.
abstract: In a subset of children experiencing prolonged febrile seizures (FSs), the most common type of childhood seizures, cognitive outcomes are compromised. However, the underlying mechanisms are unknown. Here we identified significant, enduring spatial memory problems in male rats following experimental prolonged FS (febrile status epilepticus; eFSE). Remarkably, these deficits were abolished by transient,post hocinterference with the chromatin binding of the transcriptional repressor neuron restrictive silencing factor (NRSF or REST). This transcriptional regulator is known to contribute to neuronal differentiation during development and to programmed gene expression in mature neurons. The mechanisms of the eFSE-provoked memory problems involved complex disruption of memory-related hippocampal oscillations recorded from CA1, likely resulting in part from impairments of dendritic filtering of cortical inputs as well as abnormal synaptic function. Accordingly, eFSE provoked region-specific dendritic loss in the hippocampus, and aberrant generation of excitatory synapses in dentate gyrus granule cells. Blocking NRSF transiently after eFSE prevented granule cell dysmaturation, restored a functional balance of γ-band network oscillations, and allowed treated eFSE rats to encode and retrieve spatial memories. Together, these studies provide novel insights into developing networks that underlie memory, the mechanisms by which early-life seizures influence them, and the means to abrogate the ensuing cognitive problems.SIGNIFICANCE STATEMENTWhereas seizures have been the central focus of epilepsy research, they are commonly accompanied by cognitive problems, including memory impairments that contribute to poor quality of life. These deficits often arise before the onset of spontaneous seizures, or independent from them, yet the mechanisms involved are unclear. Here, using a rodent model of common developmental seizures that provoke epilepsy in a subset of individuals, we identify serious consequent memory problems. We uncover molecular, cellular, and circuit-level mechanisms that underlie these deficits and successfully abolish them by targeted therapeutic interventions. These findings may be important for understanding and preventing cognitive problems in individuals suffering long febrile seizures.
authors.affiliation: Departments of Anatomy/Neurobiology.
authors.forename: Katelin P
authors.initials: KP
authors.lastname: Patterson
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont 05405.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Barry
authors.affiliation: Departments of Anatomy/Neurobiology.
authors.forename: Megan M
authors.identifier: 0000-0003-3240-8310
authors.initials: MM
authors.lastname: Curran
authors.affiliation: Departments of Anatomy/Neurobiology.|Pediatrics, and.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Singh-Taylor
authors.affiliation: Departments of Anatomy/Neurobiology.|Pediatrics, and.
authors.forename: Gary
authors.initials: G
authors.lastname: Brennan
authors.affiliation: Departments of Anatomy/Neurobiology.
authors.forename: Neggy
authors.identifier: 0000-0003-1023-572X
authors.initials: N
authors.lastname: Rismanchi
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont 05405.
authors.forename: Matias
authors.initials: M
authors.lastname: Page
authors.affiliation: Pediatrics, and.
authors.forename: Yoav
authors.identifier: 0000-0002-8843-1280
authors.initials: Y
authors.lastname: Noam
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont 05405.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Holmes
authors.affiliation: Departments of Anatomy/Neurobiology, tallie@uci.edu.|Pediatrics, and.|Neurology, University of California-Irvine, Irvine, California 92697-4475, and.
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003294:Seizures, Febrile / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
keywords: NRSF; epigenetics; febrile seizures; hippocampus; memory; seizures