The long-term objective of this proposal is to improve our understanding of development of the human cerebral cortex, and cortical interneurons in particular. Cortical interneurons are necessary for building and fine-tuning of the cortical microcircuitry as they provide inhibitory input to principal (pyramidal) cells. In rodents, the majority of cortical interneurons is derived from the ventral pallidum (ganglionic eminences, GE). They subsequently migrate tangentially into the dorsal cerebral cortex. In the human brain, however, several reports have shown that cortical interneurons may originate both in the GE and in the neocortical ventricular/subventricular zones. The much longer developmental period, size, complexity of the human cerebral cortex and various subtypes of interneurons implicate inter-species differences. Thus, information derived from animal models, although very useful, can not be directly applied to humans. However, to be able to cure various psychiatric and neurological disorders, we need to better understand human brain.
Three Specific Aims will be addressed: 1. Cortical interneuron's progenitors in the human fetal brain. 2. Ventral transcription factors in the human fetal brain, and 3. Do radial glia and/or intermediate progenitors contribute to human cortical interneuron population? Methods of classical histology, immunohistochemistry, in situ hybridization, and in vitro genetic manipulation methods will be used. We will relate some of the findings in the human fetal brain to the developing mouse brain so that issues relevant to species-dependent differences can be addressed. A key premise is that a diversity of cortical progenitor cells is necessary to achieve the complexity of the human cerebral cortex. The experimental approaches proposed here are not typically used to study the human fetal brain, but we expect they will yield important information about basic mechanisms regulating the initial cortical organization in humans. The knowledge about human cortical interneurons is fundamental for understanding normal developmental processes, as well as congenital and psychiatric brain disorders, such as schizophrenia or autism, and may contribute to their prevention and treatment. Having available to us a well- characterized collection of human fetal brains, an opportunity to obtain fresh tissue, and expertise in this field, we are in a favorable position to perform proposed experiments.
I propose to study the distribution and origin of human cortical interneurons, cell type involved in basic circuitry of the cerebral cortex. The experiments outlined in this application will not only improve our knowledge of normal human cortical development, but will be helpful for understanding the pathogenic mechanisms of congenital and psychiatric brain disorders, such autism and schizophrenia.
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