Description

Creating Humanized Astroglial Chimeric Mouse Brains for Modeling Down Syndrome Down syndrome (DS) arises from triplication of human chromosome 21 (HSA21) and is the mostcommon genetic cause of intellectual disability. Our understanding on neuropathophysiology of DS is mainlygained from studies in transgenic mouse models and limited human DS fetal brain tissue. However, thesestrategies have limited utility because human tissues are relatively inaccessible and the mouse models onlydemonstrate an incomplete trisomy of HSA21. These limitations have been recently circumvented by theadvent of human induced pluripotent stem cell (hiPSCs), as the iPSC technology has led to the generation ofDS patient-derived hiPSCs, which presents an unprecedented opportunity for studying the pathogenesis of DSwith unlimited human brain cells in vitro. While using the hiPSC-based in vitro model, basic aspects of thedisease phenotypes can be examined, the consequences of these events towards the formation or disruptionof neural circuits in the developing CNS can be studied only in vivo. Therefore, we propose to create ahumanized chimeric mouse model with hiPSCs for studying the neuropathophysiology of DS in vivo.Specifically, the role of DS human astrocytes will be examined because astrocytes are a major cellularconstituent in the central nervous system and play crucial roles in neuronal development and function. Indeed,using the astroglia and neurons differentiated from DS hiPSCs (DS astroglia and DS neurons), our in vitrostudy has revealed a novel and significant role of DS astroglia in causing the abnormal phenotypes of DSneurons. Recent transplantation studies demonstrated that neonatally engrafted human glial progenitor cellsdifferentiated to astroglia and oligodendroglia in the mouse brain, which largely repopulated the adult hostrodent brain, generating widespread brain chimerism. Using the established hiPSCs in our lab, here I proposeto generate chimeric mouse brains that are repopulated by only human astroglia, in the absence of any humanoligodendroglia or glial progenitor cells. By creating such humanized astroglial chimeric mouse brains, we seekto specifically dissect the role of astroglia in the DS pathogenesis in an in vivo system with intact neuralnetworks. We hypothesize that engrafted diseased DS human astroglia will show abnormal signaling activity invivo as compared to control human astroglia and this abnormal activity will further negatively regulate thesynaptic activity and plasticity of the host hippocampal neural network. In this study, Aim 1 will generatechimeric mice with these well characterized DS and control human astroglia. We will optimize thetransplantation procedure and characterize the differentiation, migration and distribution the human astroglia inthe mouse brains at ages ranging from 3 to 6 months. Aim 2 will expand to determine the Ca2+ signaling activityof the engrafted control and DS astroglia and their effects on neuronal synaptic activity and plasticity in thehippocampus. This proposed study will create a novel hiPSC-based in vivo model for studying the effects ofDS astroglia on development and formation of neural networks, and ultimately on cognitive performance of theanimals. The generation of chimeric mouse with human DS astroglia will provide new opportunities for testingdrugs that have therapeutic effects through targeting on astroglia. Building upon the iPSC technology, we alsoexpect this study to serve as a template for the investigation of a variety of neurological diseases in vivo usinghiPSC-derived astroglia.
StatusActive
Effective start/end date9/13/178/31/19

Funding

  • National Institutes of Health (NIH)

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Down Syndrome
Astrocytes
Brain
Induced Pluripotent Stem Cells
Neuroglia
Technology
Phenotype
Neurons
Chromosomes, Human, Pair 21
Chimerism
Neuronal Plasticity
Trisomy
Oligodendroglia
Human Chromosomes
Therapeutic Uses
Intellectual Disability
Transgenic Mice