Activity-dependent cholesterol biosynthesis in human-derived astrocytes regulates the functional maturation of human-derived cortical neurons
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236398 | GEO | 2023/07/21
REPOSITORIES: GEO
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Project description:Astrocytes interact closely with neurons and facilitate neuronal maturation and function by providing trophic support, regulating the extracellular environment, and engaging in a variety of inter-cellular signalling mechanisms. We have described the generation of human astrocytes and neurons from a common cortical progenitor pool, thereby recapitulating aspects of in vivo development. Firstly, we show that the iPSC-derived astrocytes exhibit many of the key molecular and functional hallmarks predicted of astrocytes. Secondly, we provide functional and transcriptomic analyses of the astrocytes’ capacity to interact with neurons both through rapid regulation of ongoing synaptic transmission as well as exerting pro-maturational effects on the synaptic networks. Transcriptional analysis included the comparison of the present RNA-seq of iPSC-derived astrocytes to other iPSC-derived astrocyte datasets as well as fetal and adult human astrocytes. We investigated differences in gene expression between our maturation-enhancing iPSC-astrocytes and iPSC-astrocytes previously shown to be unable to promote synaptic network maturation. By integrating transcriptomic data, functional genomic annotations and protein-protein interaction resources we support that astrocytic extracellular signalling is important for the ability of astrocytes to mediate functional neuronal maturation. This work provides a foundation for future investigations into astrocyte-neuron interactions in human health and disease.
2020-04-30 | GSE149598 | GEO
Project description:Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain astrocyte identity in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.
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Project description:Astrocytes and neurons coexist and interact in the CNS1,2. Given that many signaling and pathological events are protein-driven, identifying astrocyte and neuron proteomes is essential for elucidating the complex protein networks that dictate their respective contributions to physiology and disease. Here, we used cell- and subcompartment-specific proximity-dependent biotinylation3 to study the proteomes of striatal astrocytes and medium spiny neurons (MSNs) in vivo. We evaluated cytosolic and plasma membrane compartments for astrocytes and MSNs, revealing how these cells differ at the protein level and in their core signaling machinery. We assessed subcellular compartments of astrocytes including end feet and processes to reveal the molecular basis of essential astrocyte signaling and homeostatic functions. Unexpectedly, SAPAP3 proteins (gene; Dlgap3) associated with obsessive compulsive disorder (OCD) and repetitive behaviors4-11 were detected at equivalent levels in striatal astrocyte and MSN plasma membrane and cytosolic compartments. Astrocytic expression was confirmed by RNA-seq, fluorescence in situ hybridization and immunohistochemistry. Furthermore, genetic rescue experiments combined with behavioral analyses and proteomics in a mouse model4 of OCD lacking SAPAP3 revealed contributions of SAPAP3 in astrocytes and MSNs to repetitive and anxiety-related OCD behaviors. Our data define how astrocytes and neurons differ at the protein level and in their major signaling pathways, how astrocyte proteomes vary between physiological subcompartments, and how specific astrocyte and neuronal molecular mechanisms contribute to a psychiatric disease. Targeting both astrocytes and neurons together is likely to be therapeutically effective in complex CNS disorders.
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Project description:Aubert2005 - Interaction between astrocytes
and neurons on energy metabolism
Enocded non-curated model. Issues:
- Confusing equations A.41 and A.42
- Missing values for parameters Vv,0 and dHb,0
This model is described in the article:
Interaction between
astrocytes and neurons studied using a mathematical model of
compartmentalized energy metabolism.
Aubert A, Costalat R.
J. Cereb. Blood Flow Metab. 2005 Nov;
25(11): 1476-1490
Abstract:
Understanding cerebral energy metabolism in neurons and
astrocytes is necessary for the interpretation of functional
brain imaging data. It has been suggested that astrocytes can
provide lactate as an energy fuel to neurons, a process
referred to as astrocyte-neuron lactate shuttle (ANLS). Some
authors challenged this hypothesis, defending the classical
view that glucose is the major energy substrate of neurons, at
rest as well as in response to a stimulation. To test the ANLS
hypothesis from a theoretical point of view, we developed a
mathematical model of compartmentalized energy metabolism
between neurons and astrocytes, adopting hypotheses highly
unfavorable to ANLS. Simulation results can be divided between
two groups, depending on the relative neuron versus astrocyte
stimulation. If this ratio is low, ANLS is observed during all
the stimulus and poststimulus periods (continuous ANLS), but a
high ratio induces ANLS only at the beginning of the stimulus
and during the poststimulus period (triphasic behavior).
Finally, our results show that current experimental data on
lactate kinetics are compatible with the ANLS hypothesis, and
that it is essential to assess the neuronal and astrocytic
NADH/NAD+ ratio changes to test the ANLS hypothesis.
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MODEL1411210000.
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2015-02-25 | MODEL1411210000 | BioModels
Project description:Huntington’s disease (HD) is caused by expanded CAG repeats in the Huntingtin gene (HTT) that results in expression of mutant HTT proteins (mHTT) with extended polyglutamine tracts in diverse cells of the body, including striatal neurons and astrocytes. The relative contributions of neurons and astrocytes to disease pathogenesis are unknown for HD and other neurodegenerative diseases. This is a critical issue to address since it has been proposed that neuronal loss in HD and other major neurodegenerative diseases is downstream of astrocytic dysfunction that drives neuronal death. Moreover, astrocyte-to-neuron conversion is considered a promising approach in HD and other neurodegenerative diseases with little reported detriment with regards to normal astrocytic physiological functions, which are varied and extensive in health and disease. Thus, astrocytes are considered both causative and also largely replaceable in neurodegeneration, and their basic contributions to disease pathophysiology relative to neurons remain undefined in vivo. We used genetically encoded and cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and molecularly dissected neuronal and astrocytic influences on HD pathophysiology at molecular, cellular, and behavioral levels. We found that the major disease drivers were in fact neurons, with astrocytes displaying lesser loss of essential functions such as cholesterol metabolism that were downstream of greater neuronal dysfunction, which encompassed neuromodulation, synaptic, and intracellular signaling. We thus dissected the cell autonomous and non-cell autonomous mechanistic and causal contributions of both neurons and astrocytes to a complex neurodegenerative disease in vivo with wider implications for rescue and repair strategies.
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Project description:Astrocytic morphogenesis and maturation are critical steps in CNS development. The time window of astrocyte morphological development is well defined, but the molecular underpinnings are still unclear. BDNF is a critical growth factor involved in the development of the CNS, including synapse refinement. Here we demonstrate the BDNF receptor at Ntrk2 is enriched in astrocytes relative to all CNS cell populations. RNA sequencing indicates Ntrk2 falls in the top 0.001% of all gene transcripts expressed in juvenile astrocytes, almost exclusively due to truncated TrkB.T1. Astrocyte complexity is increased in the presence of BNDF in vitro, which is dependent upon the presence of TrkB.T1. Furthermore, deletion of TrkB.T1 in vivo revealed astrocytes with significantly reduced volume and branching complexities. Indicating a role for functional astrocyte maturation via BDNF/TrkB.T1 signaling, TrkB.T1 KO astrocytes do not support normal excitatory synaptogenesis. Together, these data suggest a significant role for BDNF/TrkB.T1 signaling in astrocyte morphogenesis and indicate this signaling may contribute to astrocyte regulation of neuronal synapse development.
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