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The Journal of Neuroscience, March 18, 2009, 29(11):3453-3462; doi:10.1523/JNEUROSCI.5215-08.2009
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Neurobiology of Disease
Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy
Rimante Minkeviciene,1 * Sylvain Rheims,3 * Marton B. Dobszay,5 * Misha Zilberter,5 Jarmo Hartikainen,1 Lívia Fülöp,6 Botond Penke,7 Yuri Zilberter,4,5 Tibor Harkany,5,8 Asla Pitkänen,1,2 andHeikki Tanila1,2 1A. I. Virtanen Institute, University of Kuopio, and 2Department of Neurology, Kuopio University Hospital, FIN-70211 Kuopio, Finland, 3Faculté de Sciences de Luminy, Aix Marseille Université, and 4Institut National de la Santé et de la Recherche Médicale, Institut de Neurobiologie de la Méditerranée U901, F-13000 Marseille, France, 5Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, S-17177 Stockholm, Sweden, 6Department of Medical Chemistry and 7Supramolecular and Nanostructured Materials Research Group of the Hungarian Academy of Science, University of Szeged, H-6720 Szeged, Hungary, 8Institute of Medical Sciences, College of Life Sciences & Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom
Correspondence should be addressed to Dr. Heikki Tanila, Department of Neurobiology, A. I. Virtanen Institute, University of Kuopio, P.O. Box 1627, Neulaniementie 2, FIN-70211 Kuopio, Finland. Email: Heikki.Tanila{at}uku.fi
Alzheimer's disease is associated with an increased risk of unprovoked seizures. However, the underlying mechanisms of seizure induction remain elusive. Here, we performed video-EEG recordings in mice carrying mutant human APPswe and PS1dE9 genes (APdE9 mice) and their wild-type littermates to determine the prevalence of unprovoked seizures. In two recording episodes at the onset of amyloid β (Aβ) pathogenesis (3 and 4.5 months of age), at least one unprovoked seizure was detected in 65% of APdE9 mice, of which 46% had multiple seizures and 38% had a generalized seizure. None of the wild-type mice had seizures. In a subset of APdE9 mice, seizure phenotype was associated with a loss of calbindin-D28k immunoreactivity in dentate granular cells and ectopic expression of neuropeptide Y in mossy fibers. In APdE9 mice, persistently decreased resting membrane potential in neocortical layer 2/3 pyramidal cells and dentate granule cells underpinned increased network excitability as identified by patch-clamp electrophysiology. At stimulus strengths evoking single-component EPSPs in wild-type littermates, APdE9 mice exhibited decreased action potential threshold and burst firing of pyramidal cells. Bath application (1 h) of Aβ1–42 or Aβ25–35 (proto-)fibrils but not oligomers induced significant membrane depolarization of pyramidal cells and increased the activity of excitatory cell populations as measured by extracellular field recordings in the juvenile rodent brain, confirming the pathogenic significance of bath-applied Aβ (proto-)fibrils. Overall, these data identify fibrillar Aβ as a pathogenic entity powerfully altering neuronal membrane properties such that hyperexcitability of pyramidal cells culminates in epileptiform activity.
Received Oct. 29, 2008; revised Jan. 5, 2009; accepted Feb. 8, 2009.
Correspondence should be addressed to Dr. Heikki Tanila, Department of Neurobiology, A. I. Virtanen Institute, University of Kuopio, P.O. Box 1627, Neulaniementie 2, FIN-70211 Kuopio, Finland. Email: Heikki.Tanila{at}uku.fi
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