Corthout, N. | Search bioRxiv

bioRxiv2020

Human iPSC-derived astrocytes transplanted into the mouse brain display three morphological responses to amyloid-β plaques

BackgroundIncreasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimers disease comes from molecular studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. MethodsTo address these challenges, we established an approach to study human astroglia within the context of the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived glia progenitors into neonatal brains of immunodeficient mice. ResultsXenografted (hiPSC)-derived glia progenitors differentiate into astrocytes that integrate functionally within the mouse host brain and mature in a cell-autonomous way retaining human-specific morphologies, unique features and physiological properties. In Alzheimers chimeric brains, transplanted hiPSC-derived astrocytes respond to the presence of amyloid plaques with various morphological changes that seem independent of the APOE allelic background. ConclusionIn sum, this chimeric model has great potential to analyze the role of patient-derived and genetically modified astroglia in Alzheimers disease.

neuroscience↗

bioRxiv2020

Upregulation of TRPM3 drives hyperexcitability in nociceptors innervating inflamed tissue.

Genetic ablation or pharmacological inhibition of the heat-activated cation channel TRPM3 alleviates heat hyperhyperalgesia in animal models of inflammation, but the mechanisms whereby the channel contributes to inflammatory pain are unknown. Here, we induced unilateral inflammation of the hind paw in mice, and directly compared expression and function of TRPM3 and two other heat-activated TRP channels (TRPV1 and TRPA1) in sensory neurons innervating the ipsilateral and contralateral paw. We detected increased Trpm3 mRNA levels in dorsal root ganglion neurons innervating the inflamed paw, as well as augmented TRP channel-mediated calcium responses, both in the cell bodies and the intact peripheral endings of nociceptors. Notably, inflammation provoked a pronounced increase in nociceptors co-expressing functional TRPM3 with TRPV1 and TRPA1, and pharmacological inhibition of TRPM3 caused normalization of TRPV1- and TRPA1-mediated responses. These new insights into the mechanisms underlying inflammatory heat hypersensitivity provide a rationale for developing TRPM3 antagonists to treat pathological pain.

neuroscience↗