In this study, we identified a specific role for human striatal glia in the pathogenesis of HD, by comparing the behaviour and MSN physiology of human glial chimeric mice xenografted at birth with mutant HD-expressing human hGPCs to their normal HTT hGPC-engrafted controls.
Yet the relatively greater role of human astrocytes in neural processing suggests the potential for glial pathology to wreck especial havoc within human neural circuits, with attendant implications for the human neurodegenerative disorders. Accordingly, mice neonatally engrafted with human glial progenitor cells (hGPCs), which develop brains chimeric for human astroglia and their progenitors 10, exhibit substantially enhanced activity-dependent plasticity and learning 11. Indeed, this gap in our knowledge is especially concerning in light of the marked differences between human and rodent glia human astrocytes are larger and more structurally complex than rodent glia, and influence the actions of vastly more synapses within their geographic domains 8, 9. Our lack of understanding of the role of glial pathology in HD has reflected the lack of in vivo models that permit the separate interrogation of glial and neuronal functions in HD, particularly so in humans. Yet, despite the pronounced loss of neostriatal medium spiny neurons (MSNs) in HD, and evidence of glial dysfunction 6, 7, few studies have investigated the specific contribution of glial pathology either to striatal neuronal dysfunction in HD, or more broadly, to disease phenotype. The encoded polyglutamine expansions of mutant huntingtin (mHTT) protein disrupt its normal functions and protein–protein interactions, ultimately yielding widespread neuropathology, most rapidly evident in the neostriatum. Huntington’s disease (HD) is a prototypic neurodegenerative disorder, characterized by abnormally long CAG repeat expansions in the first exon of the Huntingtin gene. Glial pathology may contribute to a broad set of neurodegenerative and neuropsychiatric diseases traditionally considered disorders of solely neuronal dysfunction 1, 2, 3, 4, 5. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder.
Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs.
The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored.
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