Dentate development in organotypic hippocampal slice cultures from p35 knockout mice

Abnormal brain development, induced by genetic influences or resulting from a perinatal trauma, has been recognized as a cause of seizure disorders. To understand how and when these structural abnormalities form, and how they are involved in epileptogenesis, it is important to generate and investigate animal models. We have studied one such model, a mouse in which deletion of the p35 gene (p35-/-) gives rise to both structural disorganization and seizure-like function. We now report that aberrant dentate development can be recognized in the organotypic hippocampal slice culture preparation generated from p35-/- mouse pups. In these p35-/- cultures, an abnormally high proportion of dentate granule cells migrates into the hilus and molecular layer, and develops aberrant dendritic and axonal morphology. In addition, astrocyte formation in the dentate gyrus is disturbed, as is the distribution of GABAergic interneurons. Although the p35-/- brain shows widespread abnormalities, the disorganization of the hippocampal dentate region is particularly intriguing since a similar pathology is often found in hippocampi of temporal lobe epilepsy patients. The abnormal granule cell features occur early in development, and are independent of seizure activity. Further, these aberrant patterns and histopathological features of p35-/- culture preparations closely resemble those observed in p35 knockout mice in vivo. This culture preparation thus provides an experimentally accessible window for studying abnormal developmental factors that can result in seizure propensity.