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The Journal of Neuroscience, October 13, 2004, 24(41):9005-9014; doi:10.1523/JNEUROSCI.2943-04.2004

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Neurobiology of Disease
Physiological and Morphological Characterization of Dentate Granule Cells in the p35 Knock-Out Mouse Hippocampus: Evidence for an Epileptic Circuit

Leena S. Patel,¹ H. Jürgen Wenzel,² and Philip A. Schwartzkroin²

¹Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195, and ²Department of Neurological Surgery, University of California, Davis, Davis, California 95616

There is a high correlation between pediatric epilepsies and neuronal migration disorders. What remains unclear is whether there are intrinsic features of the individual dysplastic cells that give rise to heightened seizure susceptibility, or whether these dysplastic cells contribute to seizure activity by establishing abnormal circuits that alter the balance of inhibition and excitation. Mice lacking a functional p35 gene provide an ideal model in which to address these questions, because these knock-out animals not only exhibit aberrant neuronal migration but also demonstrate spontaneous seizures.

Extracellular field recordings from hippocampal slices, characterizing the input-output relationship in the dentate, revealed little difference between wild-type and knock-out mice under both normal and elevated extracellular potassium conditions. However, in the presence of the GABA_A antagonist bicuculline, p35 knock-out slices, but not wild-type slices, exhibited prolonged depolarizations in response to stimulation of the perforant path. There were no significant differences in the intrinsic properties of dentate granule cells (i.e., input resistance, time constant, action potential generation) from wild-type versus knock-out mice. However, antidromic activation (mossy fiber stimulation) evoked an excitatory synaptic response in over 65% of granule cells from p35 knock-out slices that was never observed in wild-type slices. Ultrastructural analyses identified morphological substrates for this aberrant excitation: recurrent axon collaterals, abnormal basal dendrites, and mossy fiber terminals forming synapses onto the spines of neighboring granule cells. These studies suggest that granule cells in p35 knock-out mice contribute to seizure activity by forming an abnormal excitatory feedback circuit.

Key words: epilepsy; dentate granule cell; p35; recurrent excitation; intracellular labeling; neuronal migration disorder

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Received July 20, 2004; revised August 24, 2004; accepted August 25, 2004.

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