The Journal of Neuroscience, February 1, 2001, 21(3):983-998
Abnormal Morphological and Functional Organization of the
Hippocampus in a p35 Mutant Model of Cortical Dysplasia Associated with
Spontaneous Seizures
H. J.
Wenzel1,
C. A.
Robbins1,
L.-H.
Tsai3, and
P. A.
Schwartzkroin1, 2
Departments of 1 Neurological Surgery and
2 Physiology/Biophysics, University of Washington, Seattle,
Washington 98195, and 3 Howard Hughes Medical Institute and
Department of Pathology, Harvard Medical School, Boston,
Massachusetts 02115
Cortical dysplasia is a major cause of intractable epilepsy in
children. However, the precise mechanisms linking cortical malformations to epileptogenesis remain elusive. The neuronal-specific activator of cyclin-dependent kinase 5, p35, has been recognized as a
key factor in proper neuronal migration in the neocortex. Deletion of
p35 leads to severe neocortical lamination defects associated with
sporadic lethality and seizures. Here we demonstrate that
p35-deficient mice also exhibit dysplasia/ heterotopia of principal
neurons in the hippocampal formation, as well as spontaneous behavioral
and electrographic seizures. Morphological analyses using
immunocytochemistry, electron microscopy, and intracellular labeling
reveal a high degree of abnormality in dentate granule cells, including
heterotopic localization of granule cells in the molecular layer and
hilus, aberrant dendritic orientation, occurrence of basal dendrites,
and abnormal axon origination sites. Dentate granule cells of
p35-deficient mice also demonstrate aberrant mossy fiber sprouting.
Field potential laminar analysis through the dentate molecular layer
reflects the dispersion of granule cells and the structural
reorganization of this region. Similar patterns of cortical
disorganization have been linked to epileptogenesis in animal models of
chronic seizures and in human temporal lobe epilepsy. The p35-deficient
mouse may therefore offer an experimental system in which we can
dissect out the key morphological features that are causally related to epileptogenesis.
Key words:
epilepsy; dentate gyrus; granule cell dispersion; heterotopia; neuronal migration disorder; biocytin; EEG
Copyright © 2001 Society for Neuroscience 0270-6474/01/213983-16$05.00/0
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