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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Owens, David F
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University of Connecticut
Schools of Medicine
United States
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Reinchisi, Gisela; Limaye, Pallavi V; Singh, Mandakini B et al. (2013) Neurogenic potential of hESC-derived human radial glia is amplified by human fetal cells. Stem Cell Res 11:587-600
Jakovcevski, Igor; Mayer, Nicole; Zecevic, Nada (2011) Multiple origins of human neocortical interneurons are supported by distinct expression of transcription factors. Cereb Cortex 21:1771-82
Zecevic, Nada; Hu, Frances; Jakovcevski, Igor (2011) Interneurons in the developing human neocortex. Dev Neurobiol 71:18-33
Yu, Xiaojing; Zecevic, Nada (2011) Dorsal radial glial cells have the potential to generate cortical interneurons in human but not in mouse brain. J Neurosci 31:2413-20
Mo, Zhicheng; Zecevic, Nada (2009) Human fetal radial glia cells generate oligodendrocytes in vitro. Glia 57:490-8
Howard, Brian M; Zhicheng Mo; Filipovic, Radmila et al. (2008) Radial glia cells in the developing human brain. Neuroscientist 14:459-73
Mo, Zhicheng; Zecevic, Nada (2008) Is Pax6 critical for neurogenesis in the human fetal brain? Cereb Cortex 18:1455-65
Jakovcevski, I; Mo, Z; Zecevic, N (2007) Down-regulation of the axonal polysialic acid-neural cell adhesion molecule expression coincides with the onset of myelination in the human fetal forebrain. Neuroscience 149:328-37
Mo, Zhicheng; Moore, Anna R; Filipovic, Radmila et al. (2007) Human cortical neurons originate from radial glia and neuron-restricted progenitors. J Neurosci 27:4132-45
Howard, Brian; Chen, Yanhui; Zecevic, Nada (2006) Cortical progenitor cells in the developing human telencephalon. Glia 53:57-66

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