Analysis of the role of Reelin in mouse brain development: Reelin positive non-gabaergic populations and impact of haploinsufficience on neuronal morpology

Reelin, a large extracellular matrix protein responsible for migration and laminar positioning of neurons during brain development, has been implicated in the pathogenesis of schizophrenia and autism. There are extensive populations that have been identified in the adult mouse brain which contain cells secreting Reelin; previously these neurons were believed to be almost exclusively GABAergic. We used immunohistochemistry to reveal multiple groups of Reelin positive neurons that are not GABAergic. Specifically, we used Reelin and GABA antibodies or Vgat cre::Ai9 tdTomato to analyze whether Reelin positive cells are indeed GABAergic. Populations of Reelin positive, non-GABAergic were found in the olfactory bulb and piriform cortex; the perforant pathway; the entorhinal cortex, stratum lacunosum-moleculare of the hippocampus proper, and the dentate gyrus; lastly a small population was found in layer V of the visual cortex. These results suggest Reelin signaling may directly modulate excitatory synaptic circuits in the postnatal brain. In heterozygous reeler multiple morphological abnormalities were identified compared to wild type littermates. Branched analysis revealed a marked decrease in basal dendrite nodes in layer V cells the heterozygous reeler motor cortex and hippocampus as well as a decrease in basal length in the hippocampus. A detailed Sholl analysis indicated abnormalities in both the cortex and hippocampus of the heterozygous reeler. In the cortex we found decreased basal nodes and number of intersections as well as length at specific compartments of neuronal dendritic structure. More significant differences were found in the hippocampus, which showed a decreased total number of intersections as well as decreased intersections length of CA1 neurons. Changes in both the cortex and the hippocampus of the heterozygous brains were comparable to the homozygous reeler mutant. These findings point to underlying neuronal morphological correlates for the electrophysiological changes found in homozygous reeler mice and the physiological abnormalities exhibited in heterozygous reeler mice