Astrocyte heterogeneity and interactions with local neural circuits

Holt, Matthew

doi:10.1042/ebc20220136

Cited by 31 publications

(19 citation statements)

References 115 publications

(148 reference statements)

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“…This work also substantiates the earlier hypothesis that astrocytes might be the principal CNS targets of NA McCarthy, 1989, 1992;Stone and Ariano, 1989). In future studies, it will be interesting to determine if α1-NAR signaling through astrocytes has the same consequences for neuromodulation in brain regions other than V1, especially considering that astrocyte heterogeneity, both between and within CNS regions, has emerged as an important factor defining astrocyte functions (Bayraktar et al, 2020;Pestana et al, 2020;Holt, 2023). For instance, earlier work has shown astrocytes in different CNS regions respond to α1-NAR activation, albeit with [Ca 2+ ] transients of different kinetics (Batiuk et al, 2020;Pham et al, 2020).…”

Section: Discussionsupporting

confidence: 85%

The astrocyte α1-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex

Wahis

Akkaya

Kirunda

et al. 2023

Preprint

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Noradrenaline (norepinephrine) is known to modulate many physiological functions and behaviors. In this study, we tested to what extent astrocytes, a type of glial cell, participate in noradrenergic signaling in mouse primary visual cortex (V1). Astrocytes are essential partners of neurons in the central nervous system. They are central to brain homeostasis, but also dynamically regulate neuronal activity, notably by relaying and regulating neuromodulator signaling. Indeed, astrocytes express receptors for multiple neuromodulators, including noradrenaline, but the extent to which astrocytes are involved in noradrenergic signaling remains unclear. To test whether astrocytes are involved in noradrenergic neuromodulation in mice, we knocked down the major noradrenaline receptor in astrocytes, the alpha 1A-adrenoreceptor. Using this model, we found that the alpha 1A-adrenoreceptor is involved in triggering intracellular calcium transients in astrocytes, which are generally thought to underlie astrocyte function. To test if impaired alpha 1A-adrenoreceptor signaling in astrocytes affected the function of neuronal circuits in V1, we used electrophysiological measurements and found that noradrenergic signaling through astrocyte alpha 1A-adrenoreceptor controls the basal level of inhibition and regulates plasticity in V1 by potentiating synaptic responses in circuits involved in visual information processing.

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Section: Discussionsupporting

confidence: 85%

The astrocyte α1-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex

Wahis

Akkaya

Kirunda

et al. 2023

Preprint

Self Cite

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“…Astrocyte heterogeneity has been an emerging consensus in recent studies (reviewed by Holt, 2023). Molecular characterization that captures mRNA distributed in astrocyte processes, for example, across cortical layers, describes differences in degree, rather than kind (Farhy‐Tselnicker et al., 2021).…”

Section: Discussionmentioning

confidence: 99%

Astrocyte ensheathment of calyx‐forming axons of the auditory brainstem precedes accelerated expression of myelin genes and myelination by oligodendrocytes

Heller,

Kolson,

Brandebura

et al. 2023

J of Comparative Neurology

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Early postnatal brain development involves complex interactions among maturing neurons and glial cells that drive tissue organization. We previously analyzed gene expression in tissue from the mouse medial nucleus of the trapezoid body (MNTB) during the first postnatal week to study changes that surround rapid growth of the large calyx of Held (CH) nerve terminal. Here, we present genes that show significant changes in gene expression level during the second postnatal week, a developmental timeframe that brackets the onset of airborne sound stimulation and the early stages of myelination. Gene Ontology analysis revealed that many of these genes are related to the myelination process. Further investigation of these genes using a previously published cell type‐specific bulk RNA‐Seq data set in cortex and our own single‐cell RNA‐Seq data set in the MNTB revealed enrichment of these genes in the oligodendrocyte lineage (OL) cells. Combining the postnatal day (P)6–P14 microarray gene expression data with the previously published P0–P6 data provided fine temporal resolution to investigate the initiation and subsequent waves of gene expression related to OL cell maturation and the process of myelination. Many genes showed increasing expression levels between P2 and P6 in patterns that reflect OL cell maturation. Correspondingly, the first myelin proteins were detected by P4. Using a complementary, developmental series of electron microscopy 3D image volumes, we analyzed the temporal progression of axon wrapping and myelination in the MNTB. By employing a combination of established ultrastructural criteria to classify reconstructed early postnatal glial cells in the 3D volumes, we demonstrated for the first time that astrocytes within the mouse MNTB extensively wrap the axons of the growing CH terminal prior to OL cell wrapping and compaction of myelin. Our data revealed significant expression of several myelin genes and enrichment of multiple genes associated with lipid metabolism in astrocytes, which may subserve axon wrapping in addition to myelin formation. The transition from axon wrapping by astrocytes to OL cells occurs rapidly between P4 and P9 and identifies a potential new role of astrocytes in priming calyceal axons for subsequent myelination.

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“…Unlike peripheral metastases, the emergence of BM depends on a plethora of environmental cues such as the spatiotemporal availability of factors that are provided by cells of the TME, supporting or repressing tumor cell growth 2 . Moreover, single-cell RNA sequencing (scRNAseq) studies have confirmed regional heterogeneity of astrocytes 3 , oligodendrocytes 4 and microglia 5,6 in healthy human brains. Particularly, astrocytes and microglia adopt a reactive cell state 7,8 that accompanies secretion of pro- and anti-inflammatory factors under pathological conditions 9, 10 .…”

Section: Introductionmentioning

confidence: 95%

MET receptor activation by stromal cells serves as promising target in melanoma brain metastases

Redmer,

Schumann,

Peters

et al. 2023

Preprint

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The development of brain metastases hallmarks disease progression in 20-40% of melanoma patients and is a serious obstacle to therapy. Understanding the processes involved in the development and maintenance of melanoma brain metastases (MBM) is critical for the discovery of novel therapeutic strategies. Here, we generated transcriptome and methylome profiles of MBM showing high or low abundance of infiltrated Iba1high tumor-associated microglia and macrophages (TAMs). Our survey identified potential prognostic markers of favorable disease course and response to immune checkpoint inhibitor (ICi) therapy, among them APBB1IP and the interferon-responsive gene ITGB7. In MBM with high ITGB7/APBB1IP levels, the accumulation of TAMs correlated significantly with the immune score. Signature-based deconvolution of MBM via single sample GSEA revealed enrichment of interferon-response and immune signatures and revealed inflammation, stress and MET receptor signaling. MET receptor phosphorylation/activation maybe elicited by inflammatory processes in brain metastatic melanoma cells via stroma cell-released HGF. We observed phospho-METY1234/1235 in a subset of MBM and observed marked response of brain metastasis-derived cell lines (BMCs) that lacked druggable BRAF mutations or developed resistance to BRAF inhibitors (BRAFi) in vivo to MET inhibitors PHA-665752 and ARQ197 (tivantinib). In summary, the activation of MET receptor in brain colonizing melanoma cells by stromal cell-released HGF may promote tumor cells self-maintenance and expansion might counteract ICi therapy. Therefore, therapeutic targeting of MET possibly serves as promising strategy to control intracranial progressive disease and improve patient survival.

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Astrocyte heterogeneity and interactions with local neural circuits

Cited by 31 publications

References 115 publications

The astrocyte α1-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex

The astrocyte α1-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex

Astrocyte ensheathment of calyx‐forming axons of the auditory brainstem precedes accelerated expression of myelin genes and myelination by oligodendrocytes

MET receptor activation by stromal cells serves as promising target in melanoma brain metastases

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