Abstracts

RATIONALE: The p35 knockout mouse (p35 -/-) provides a model of cortical dysplasia (CD) that exhibits spontaneous epileptic activity. In these animals, there is not only a disturbance in cortical lamination, but also a dispersion of the granule cell (GC) layer of the dentate gyrus. Characterization of electrophysiological consequences of GC layer disorganization in p35 -/- mice should provide insight into the CD-epilepsy relationship. METHODS: Individual GCs from hippocampal slices of +/+ and -/- mice were intracellularly labeled with biocytin, and morphological analyses were performed using both histochemistry and electron microscopy (EM). Extracellular field and intracellular recording techniques were used to examine the effects of aberrant morphology on the population discharge of the dentate gyrus and intrinsic properties of GCs. RESULTS: Morphological analysis of biocytin-labeled GCs revealed abnormalities in neuron shape, localization and connectivity. EM revealed MF boutons heterotopically localized within the GC and ML layers, forming synaptic contacts onto GC bodies and with GC dendritic spines. In hippocampal slices, a laminar profile of synaptic responses recorded through the superior blade of the dentate gyrus demonstrated differences between +/+ and -/- mice consistent with the dispersion of the GC layer. I/O curves, based on field EPSPs and population spikes, did not indicate an obvious difference in synaptic drive onto GCs in the -/- mice; however, in 6 mM K+, responses from -/- animals suggest a greater sensitivity to K+ accumulation. Initial studies showed little difference in intrinsic neuronal properties between +/+ and -/- GCs (mean RMP = -78 vs -81 mV; Rin = 48 vs 47 M?; AP ampl = 97 vs 86 mV; AP thresh = -51 vs -53 mV; n= 10+/+, 10-/-). CONCLUSIONS: In mice, loss of the p35 protein results in CD associated with spontaneous seizures. The cortical disorganization includes salient morphological abnormalities in the dentate gyrus similar to those seen in human TLE. In vitro analysis of dysplastic dentate gyrus has thus far revealed only subtle functional abnormalities in the p35 -/- tissue. Supported by NIH NS18895.