Presentation Abstract

Program#/Poster#: 43.2/D23
Title: Emergence of a seizure phenotype in aged apoE4 targeted replacement mice
Location: South Hall A
Presentation Time: Saturday, Oct 17, 2009, 2:00 PM - 3:00 PM
1Neurosci. Discovery, Eli Lilly and Co., Indianapolis, IN; 2Sleep Res., Eli Lilly and Co., Windlesham, United Kingdom; 3Neurol. and Hope Ctr. for Neurolog. Disorders, Washington Univ., St. Louis, MO; 4Medicine, Div. of Geriatrics, Durham VA Med. Ctr., Duke Univ., Durham, NC
Abstract: The epsilon 4 (E4) polymorphism of apolipoprotein E (apoE) is the most significant genetic risk factor for developing late-onset Azhiemer’s Disease (AD). Neurodegeneration in AD may result in aberrant neuronal excitability. Abnormal resting electroencephalography (EEG) activity has been reported in AD, and the E4 polymorphism exacerbates these abnormalities. Unprovoked seizures have been reported in as many as 20% of AD patients and are more prevalent when familial AD mutations are present. Cognitively normal apoE4 carriers under certain types of stress exhibit abnormal EEG activity and several mouse models of AD exhibit non-convulsive seizure activity in the hippocampus. In the course of studying targeted replacement apoE (TR-E) mice, we observed the emergence of a seizure phenotype in aged TR-E4 mice. Clonic seizures began to develop between 5 and 12 months of age in the TR-E4 mice and were triggered by mild stress (e.g. being placed in a clean cage). To fully document this, we blindly rated the behavioral seizure phenotype in a large cohort of aged (~1yr; n = 40 TR-E2, 40 TR-E3, 60 TR-E4) and young (12 wks old: n = 35 TR-E2, 35 TR-E3, 35 TR-E4, 35 EKO) mice. Approximately 65% of aged TR-E4 mice displayed a clinical seizure phenotype. Most seizures were mild and consisted of freezing behavior followed by multiple myoclonic jerks, while ~15% of TR-E4 mice had more severe seizures that included at least forelimb clonus. Myoclonic jerks were recorded in ~1% of aged TR-E2 and TR-E3 mice, while no events occurred in young mice of any genotype. Over several months the seizure phenotype progressively developed and persisted in the same mice for the remainder of their lifespan. Some mice never developed a seizure phenotype while the seizure phenotype in others was so severe it occasionally resulted in death. To relate the seizure phenotype to abnormal neuronal activity, dual platinum-iridium depth EEG electrodes were implanted into the hippocampus of old TR-E4 mice and controls. Power analysis of spectral recordings revealed that aged TR-E4 mice (n=5) exhibited frequent bursts of synchronous EEG spikes at frequencies between 5-10 Hz at least 32.5% of the time, whereas similar peaks in young wild type B6/SJL control mice (n=4) occurred only 0.4% of the time. Aged TR-E2 and TR-E3 mice do not have this type of prolonged, abnormal EEG activity, however these genotypes may display other EEG abnormalities which are currently under investigation. Neo-Timm staining of aged TR-E4 animals did not reveal any overt changes in mossy fiber sprouting. Further studies to identify the underlying mechanisms of this seizure phenotype in TR-E4 mice and how it relates to AD pathology are underway.
Disclosures:   J.M. Hunter, Eli Lilly and Company, A. Employment (full or part-time); J.R. Cirrito, Eli Lilly and Company, C. Other Research Support (receipt of drugs, supplies, equipment or other in-kind support); J. Restivo, Eli Lilly and Company, C. Other Research Support (receipt of drugs, supplies, equipment or other in-kind support); R. Kinley, Eli Lilly and Company, A. Employment (full or part-time); P.M. Sullivan, None; D.M. Holtzman, Eli Lilly and Company, Other; S.M. Paul, Eli Lilly and Company, A. Employment (full or part-time).
Support: Eli Lilly and Company
[Authors]. [Abstract Title]. Program No. XXX.XX. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009. Online.

2009 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.

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