Behavioral Resilience and Sensitivity to Locally Restricted Cortical Migration Deficits Induced by In Utero Knockdown of Disabled-1 in the Adult Rat

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Irregular neuronal migration plays a causal role in mental illnesses such as schizophrenia and autism, but the very nature of the migration deficits necessary to evoke adult behavioral changes is unknown. Here, we used in utero electroporation (IUE) in rats to induce a locally restricted, cortical migration deficit by knockdown of disabled-1 (Dab1), an intracellular converging point of the reelin pathway. After birth, selection of successfully electroporated rats by detection of in vivo bioluminescence of a simultaneously electroporated luciferase gene correlated to and was thus predictive to the number of electroporated neurons in postmortem histochemistry at 6 months of age. Rat neurons silenced for Dab1 did not migrate properly and their number surprisingly decreased after E22. Behavioral tests at adult ages (P180) revealed increased sensitivity to amphetamine as well as decreased habituation, but no deficits in memory tasks or motor functions. The data suggest that even subtle migration deficits involving only ten-thousands of cortical neurons during neurodevelopment can lead to lasting behavioral and neuronal changes into adulthood in some very specific behavioral domains. On the other hand, the lack of effects on various memory-related tasks may indicate resilience and plasticity of cognitive functions critical for survival under these specific conditions.

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