Cortical dysplasia can result from genetic causes that produce cortical malformations such as lissencephaly or double cortex, or from environmental causes resulting in dysplasias due to cocaine, alcohol, toxins, or radiation exposure. Dysplasia also results from a combination of genetic and environmental effects, such as schizophrenia. In humans, dysplastic cortex correlates with a range of structural findings, including thinner cortical mantles and abnormal positioning of cells. We developed a ferret model of cortical dysplasia that interrupts neurogenesis of cells destined for layer 4 of neocortex. To do this, the antimitotic methylazoxy methanol (MAM) is injected into a pregnant ferret on embryonic day 33 (E33). This results in a cohort of cells (those normally populating layer 4) failing to migrate into the neocortex, while those generated before and after the interruption appear relatively normal. Disruption of the birth and migration of cells destined for cortical layer 4 has highly specific consequences and provides an excellent model of the effects of an epigenetic factor on cortical development. The resulting constellation of symptoms in ferret somatosensory cortex include abnormal thalamic terminations, redistribution of GABAA receptors, and disrupted ability to process simple and complex sensory stimuli. GABAergic neurons arising from the ganglionic eminence (GE) are disoriented en route and have altered distributions in mature MAM-treated animals. The current proposal assesses factors important for the migration of neurons from the GE and determines whether cues arise from the cortex or are intrinsic to the migrating neurons.
Two Specific Aims that address the following questions.
The first aim asks: What factors are important for normal migration of neurons arising from the ganglionic eminence and do they differ for those that guide neurons migrating from the VZ? Can we define characteristics of GE cells more explicitly in normal and MAM-treated cortex? The second aim asks: Can layer 4 impaired cortex be repaired? Can functional activity be restored? Can we use neurons of multiple origin to repair MAM-treated cortex? Can we create true neural progenitor cells? These studies will use organotypic cultures and transplantation of neural progenitor cells into neonatal ferrets. We expect these experiments to lead to novel ideas about factors mediating tangential migration of neurons arising from the GE and the potential of ferret progenitor cells to repair to damaged cortex.
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