Aberrant dentate gyrus cytoarchitecture and fiber lamination in Lis1 mutant mice

Mutant mice with a heterozygous deletion of LIS1, show varying degrees of hippocampal abnormality and enhanced excitability. To examine how LIS1 affects cytoarchitecture and fiber lamination in dentate gyrus (DG), we performed a series of immunohistochemistry studies. By using different neuronal- and glial-specific antibodies, we found that the majority of hippocampal cell populations were affected by heterozygous mutation of LIS1; some reelin-positive Cajal-Retzius cells were left undisturbed. Granule cell dispersion was significant in hippocampal sections from List-deficient mice. However, the fiber termination of commissural/associational fibers and mossy fibers appeared relatively compact despite obvious granule cell dispersion and CA1-CA3 pyramidal cell disorganization. vGlutl-immunoreactive axon terminals were found aberrantly traversing the dispersed granule cell layer. Consistent with previous observations, we also found that immature granule cells in List mutants, here stained with antibodies to doublecortin (DCX) and Mash-1, are aberrantly located and bear an abnormal cellular morphology. Our findings suggest that LIS1 mutants exhibit abnormal cell positioning and aberrant hippocampal neurogenesis, but maintain relatively normal fiber termination patterns. The functional consequences of hippocampal granule cell dispersion could offer critical insight to the epileptic and cognitive disorder associated with LIS1 haploinsufficiency. 2008 Wiley-Liss, Inc.