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The Journal of Neuroscience, April 1, 2000, 20(7):2439-2450

Hippocampal Abnormalities and Enhanced Excitability in a Murine Model of Human Lissencephaly

Mark W. Fleck1, Shinji Hirotsune2, Michael J. Gambello2, Emily Phillips-Tansey1, Gregory Suares1, Ronald F. Mervis3, Anthony Wynshaw-Boris2, and Chris J. McBain1

1 Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, 2 Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, and 3 Neuro-Cognitive Research Labs, Columbus, Ohio 43212

Human cortical heterotopia and neuronal migration disorders result in epilepsy; however, the precise mechanisms remain elusive. Here we demonstrate severe neuronal dysplasia and heterotopia throughout the granule cell and pyramidal cell layers of mice containing a heterozygous deletion of Lis1, a mouse model of human 17p13.3-linked lissencephaly. Birth-dating analysis using bromodeoxyuridine revealed that neurons in Lis1+/- murine hippocampus are born at the appropriate time but fail in migration to form a defined cell layer. Heterotopic pyramidal neurons in Lis1+/- mice were stunted and possessed fewer dendritic branches, whereas dentate granule cells were hypertrophic and formed spiny basilar dendrites from which the principal axon emerged. Both somatostatin- and parvalbumin-containing inhibitory neurons were heterotopic and displaced into both stratum radiatum and stratum lacunosum-moleculare. Mechanisms of synaptic transmission were severely disrupted, revealing hyperexcitability at Schaffer collateral-CA1 synapses and depression of mossy fiber-CA3 transmission. In addition, the dynamic range of frequency-dependent facilitation of Lis1+/- mossy fiber transmission was less than that of wild type. Consequently, Lis1+/- hippocampi are prone to interictal electrographic seizure activity in an elevated [K+]o model of epilepsy. In Lis1+/- hippocampus, intense interictal bursting was observed on elevation of extracellular potassium to 6.5 mM, a condition that resulted in only minimal bursting in wild type. These anatomical and physiological hippocampal defects may provide a neuronal basis for seizures associated with lissencephaly.

Key words: lissencephaly; platelet-activating factor acetylhydrolase; knockout mouse; hippocampus; bromodeoxyuridine; Golgi; epilepsy; potassium

Copyright © 2000 Society for Neuroscience  0270-6474/00/2072439-12$05.00/0


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