STEP regulation of seizure thresholds in the hippocampus

Summary Purpose: To investigate whether striatal enriched protein tyrosine phosphatase (STEP) influences ictogenesis. Methods: STEP knockout mice were compared to wild‐type (WT) mice in pilocarpine‐induced seizures. Hippocampal slices were also prepared from these two mouse populations, allowing the examination of ictal‐like stimulation in these slices using calcium imaging and electrophysiologic recordings. Key Findings: To examine seizure thresholds, increasing doses of pilocarpine were administered to adult mice and seizures were scored behaviorally. Significantly fewer STEP knockout mice developed seizures that progressed to the stage of status epilepticus compared to WT mice. To examine potential differences in neural circuits that might account for this finding, seizure‐like activity was induced in hippocampal slices. Electrical stimulation of the hippocampal–entorhinal cortex pathway in STEP knockout mice resulted in less activation of the dentate gyrus granule cell layer (GCL), but greater activation of the hilus in STEP knockouts, compared with heterozygous slices. Significance: STEP deficiency is associated with higher seizure thresholds. The locus of these effects appears to include the dentate gyrus granule cell layer and hilus.