Astrocyte lineage cells are essential for functional neuronal differentiation and synapse maturation in human iPSC-derived neural networks

Simon D. Klapper, Pretty Garg, Sushma Dagar, Kerstin Lenk, Kurt Gottmann, Katja Nieweg

    Research output: Contribution to journalArticleScientificpeer-review

    8 Citations (Scopus)

    Abstract

    Human astrocytes differ dramatically in cell morphology and gene expression from murine astrocytes. The latter are well known to be of major importance in the formation of neuronal networks by promoting synapse maturation. However, whether human astrocyte lineage cells have a similar role in network formation has not been firmly established. Here, we investigated the impact of human astrocyte lineage cells on the functional maturation of neural networks that were derived from human induced pluripotent stem cells (hiPSCs). Initial in vitro differentiation of hiPSC-derived neural progenitor cells and immature neurons (glia+ cultures) resulted in spontaneously active neural networks as indicated by synchronous neuronal Ca2+ transients. Depleting proliferating neural progenitors from these cultures by short-term antimitotic treatment resulted in strongly astrocyte lineage cell-depleted neuronal networks (glia− cultures). Strikingly, in contrast to glia+ cultures, glia− cultures did not exhibit spontaneous network activity. Detailed analysis of the morphological and electrophysiological properties of neurons by patch clamp recordings revealed reduced dendritic arborization in glia− cultures. In addition, a reduced action potential frequency upon current injection in pyramidal-like neurons was observed, whereas the electrical excitability of multipolar neurons was unaltered. Furthermore, we found a reduced dendritic density of PSD95-positive excitatory synapses, and more immature properties of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) miniature excitatory postsynaptic currents (mEPSCs) in glia− cultures, suggesting that the maturation of glutamatergic synapses depends on the presence of hiPSC-derived astrocyte lineage cells. Intriguingly, addition of the astrocyte-derived synapse maturation inducer cholesterol increased the dendritic density of PSD95-positive excitatory synapses in glia− cultures.

    Original languageEnglish
    Pages (from-to)1893-1909
    Number of pages17
    JournalGlia
    Volume67
    Issue number10
    DOIs
    Publication statusPublished - 2019
    Publication typeA1 Journal article-refereed

    Keywords

    • human iPSCs
    • iPSC-derived astrocyte lineage cells
    • network function
    • neuronal differentiation
    • synapse maturation

    Publication forum classification

    • Publication forum level 2

    ASJC Scopus subject areas

    • Neurology
    • Cellular and Molecular Neuroscience

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