Gyrencephalic Model for Neurodevelopmental Disease and Postnatal Cortical Therapeutic Interventions

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PROJECT SUMMARY Cortical inhibitory neurons (CIN) are a neuronal subpopulation that have been strongly implicated in the pathogenesis of neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD)1. We recently published evidence of robust CIN migration in the postnatal human brain2, in a population called the Arc, that contributes to the cortical network in the prefrontal cortex and cingulate during the first months of life. The presence of this migratory population demonstrates that the human cortex remains dynamic in the perinatal period, the time before and after birth, and raised the need to find methods to interrogate the functional importance of “late-migrating” neurons. Perinatal human cortical development, however, is incompletely represented in the lissencephalic (agyric) rodent brain and brain tissues from this period are scarce. This has left a fundamental gap in human developmental neuroscience. The long-term goal of my research is to understand the development of the gyrated neocortex during the perinatal period, the weeks immediately before and after birth, and how disruption during that time can lead to neuropsychiatric conditions such as ASD. Our central hypothesis is that CIN continue to travel perinatally to multiple cortical regions, and that disruption of this migration contributes to abnormal social behaviors, a hallmark phenotype in ASD. To test this, we will develop the piglet cortex, which closely mimics the human neocortex, as a model to investigate the molecular diversity of CIN migrating in the perinatal brain. We will also perform birthdating experiments to determine if postnatal stem cell divisions continue to generate CIN after birth. Lastly, we will generate a conditional piglet model that specifically removes expression of the Reelin receptor, (very low density lipoprotein receptor) VLDLR, implicated in ASD etiology3,4, within a subpopulation of “late-migrating” CIN. The cellular and behavioral consequences of interrupting Reelin signaling will be examined. The proposed studies will identify distinctive properties of migratory CIN and aim to establish a novel approach to investigate ASD. By creating a more faithful model of the human cortex, we can establish the cellular processes that are needed late in cortical development and identify new ways to therapeutically influence nerve cells, even after birth.