Human evolution has been accompanied by a diversification of astrocytic phenotype and function, that has contributed to species-specific aspects of both human brain function and disease. As such, the development of human astrocytic complexity has paralleled the appearance in evolution of psychiatric disorders unique to humans - the schizophrenias in particular. Yet despite this correlative suggestion that astrocytic pathology might contribute to the disordered thought of schizophrenia, the role of astroglial pathology in its pathogenesis has been difficult to study, in part because of the lack o animal models of human glial pathophysiology. We propose to overcome this limitation, using a new model of human glial-chimeric mouse brains that we have developed, paired with our newly-developed protocols for efficiently and reliably generating astrocytes from patient-derived human induced pluripotential cells (hiPSCs). Using mice neonatally engrafted with glial progenitor cells (GPCs) derived from hiPSCs generated from schizophrenic patients, we will assess the specific contributions of schizophrenic patient-derived astrocytes to disease pathogenesis. In these human glial chimeric mouse brains, the vast majority of resident glia are replaced by human GPC-derived astrocytes and their progenitors, allowing human glial physiology, gene expression, and effects on neural function to be assessed in live adult mice. By pairing this chimerization approach with protocols that we have developed for both generating and purifying GPCs and astrocytes from hiPSCs, and using hiPSC lines produced from patients with juvenile-onset schizophrenia, we will produce mice whose resident glia are largely derived from patients with schizophrenia.
In Aim 1, we will assess the relative effects of these schizophrenia-associated astrocytes upon glial syncytial transmission within the cortices of the chimeric mice.
In Aim 2, we will next assess the synaptic plasticity of the chimeric mice, as well as the effects of schizophrenia-derived glial chimerization upon their behavioral phenotype and responses to pharmacological stressors.
In Aim 3, we will sort engrafted astroglia from the brains into which they have integrated, so as to assess the gene expression patterns of schizophrenic iPSC-derived astrocytes, relative to those of normal hiPSC-derived glia. By means of this multimodal approach, we hope to define the disease-specific effects, gene expression patterns, and paracrine toxicities of schizophrenic hiPSC-derived astrocytes relative to normal hiPSC-derived glia. These diverse lines of investigation should provide us great insight into the species- and cell type-specific roles of human astrocytes in the pathogenesis of schizophrenia. At the same time, by providing a new human glial chimeric model system, new cellular reagents in the form of schizophrenic patient-derived astrocytes, and new gene expression databases covering schizophrenic hiPSC-derived astrocytes, this project should allow us to make available to the field a broad and exciting new set of tools, capabilities and databases. Together, these should greatly accelerate our understanding of human glial dysfunction in the pathogenesis of schizophrenia.

Public Health Relevance

The evolution of species-specific functions and competencies of astrocytes may have been critical to human brain evolution, and to the development of human intellect and creativity. A corollary of this observation is that human astrocytic pathology might contribute to the development of behavioral and psychiatric disorders, most especially to schizophrenia, a uniquely human disease. We have developed mice whose brains have been substantially chimerized with human astroglia, as a means by which to study the contribution of astrocytes to human psychopathology, as well as to cognition. In the proposed experiments, we will compare the physiology and communication, effects on neural transmission and behavior, and gene expression in vivo, of astrocytes generated from iPS cells derived from patients with schizophrenia, to those derived from normal controls.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH099578-02
Application #
8629793
Study Section
Special Emphasis Panel (ZMH1-ERB-M (06))
Program Officer
Panchision, David M
Project Start
2013-03-05
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$580,612
Indirect Cost
$169,949
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Goldman, Steven A (2017) Patience pays in spinal repair. J Clin Invest 127:3284-3286
Windrem, Martha S; Osipovitch, Mikhail; Liu, Zhengshan et al. (2017) Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia. Cell Stem Cell 21:195-208.e6
Goldman, Steven A (2017) Progenitor cell-based treatment of glial disease. Prog Brain Res 231:165-189
Khakh, Baljit S; Beaumont, Vahri; Cachope, Roger et al. (2017) Unravelling and Exploiting Astrocyte Dysfunction in Huntington's Disease. Trends Neurosci 40:422-437
Osorio, M Joana; Goldman, Steven A (2016) Glial progenitor cell-based treatment of the childhood leukodystrophies. Exp Neurol 283:476-88
Liang, Qiming; Luo, Zhifei; Zeng, Jianxiong et al. (2016) Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. Cell Stem Cell 19:663-671
Benraiss, Abdellatif; Wang, Su; Herrlinger, Stephanie et al. (2016) Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nat Commun 7:11758
Goldman, Steven A (2016) Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking. Cell Stem Cell 18:174-88
Zhao, Chuntao; Deng, Yaqi; Liu, Lei et al. (2016) Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation. Nat Commun 7:10883
Nedergaard, Maiken; Goldman, Steven A (2016) BRAIN DRAIN. Sci Am 314:44-9

Showing the most recent 10 out of 28 publications