Identification of regional molecular markers in the cortex, hippocampus, and amygdala for fine structural analysis in animal models of autism

Background: Microscopically, autistic patients have been reported to show alterations in the neocortex, hippocampus, and amygdala. The precise nature of these abnormalities is largely undefined due to limited sample size and limited resolution of traditional histological techniques. Animal models have been generated to gain insight into how known etiologic factors contribute to changes in brain structure and function. Analysis of neuropathology in these models has also been limited by the resolution of Nissl stains and the paucity of histological methods for identifying unique cell populations.

Objectives: To identify molecular markers which delineate specific neuroanatomical subregions and neuronal subtypes within the cortex, hippocampus, and amygdala for analysis of fine cytoarchitecture.

Methods: To identify gene markers that delineate anatomical boundaries we mined the in situ hybridization (ISH) expression patterns of over 20,000 transcripts contained in the Allen Brain Atlas. We identified the genes that most specifically demarcate individual cortical layers, and subregions of the hippocampus and amygdala. ISH expression patterns were then analyzed during development to determine when this specificity is first observed. The Allen Institute has also generated ISH data for ~600 genes in human visual (BA 17/18) and temporal cortex (BA 21/22).These data were analyzed to identify genes that delineate discrete populations of excitatory and inhibitory cell types in human cortex.

Results: This approach has led to the identification of molecular markers that are uniquely expressed in discrete brain regions in mouse and human brain. These markers are currently being used to analyze cytoarchitecture in animal models of autism including the Mecp2^308/y, Fmr1 KO, and Ube3a KO mice.

Conclusions:  These techniques will allow us to more clearly define neuroanatomical abnormalities in animal models. Cell type-specific markers in human neocortex will also allow an analysis of fine cortical cytoarchitecture in postmortem tissue from patients with autism in the future.