Neuropathology of the cerebral cortex observed in a range of animal models of prenatal cocaine exposure may reflect alterations in genes involved in the Wnt and cadherin systems

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Abstract
Several recent reports show that the cerebral cortex in humans and animals with altered expressions of Wnt/cadherin network‐associate molecules display cytoarchitectural abnormalities reminiscent of cortical dysplasias seen in some (mouse‐, rat‐, and monkey‐based) animal models of prenatal cocaine exposure. Therefore, we employed oligo microarrays followed by real‐time RT‐PCR to compare expressions of genes involved in Wnt and cadherin systems in the cerebral wall of 18‐day‐old (E18) fetuses from cocaine‐treated (20 mg/kg cocaine, s.c., b.i.d., E8–18) and drug‐naive (saline, s.c.) mice. The pregnant mice chronically treated with cocaine in the above‐described manner represent one of the animal models producing offspring with widespread cortical dysplasias. Out of more than 150 relevant genes in the arrays, 32 were upregulated and 9 were downregulated in cocaine‐exposed fetuses. The majority of these genes (30 out of 41) were similarly affected in the frontal and occipital regions of the cerebral wall. We also used Western immunoblotting to examine the ability of cocaine to regulate the protein levels of β‐catenin, the key functional component of both Wnt and cadherin systems. While the total cell levels of β‐catenin were increased throughout the cerebral wall of cocaine‐exposed fetuses, its nuclear (gene‐transcription driving) levels remained unaltered. This suggests a transcription‐unrelated role for cocaine‐induced upregulation of this protein. Overall, our findings point to an intriguing possibility that that cerebral cortical dysplasias observed in several animal models of prenatal cocaine exposure may be at least in part related to alterations in the Wnt/cadherin molecular network. Synapse 56:105–116, 2005.