ADGRB1 contributes to astrocyte-mediated phagocytosis of excitatory synapses
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ABSTRACT:
PROVIDER: PRJNA1073438 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27871792_1.fastq.gz | Fastqsanger.gz | |||
| SRR27871792_2.fastq.gz | Fastqsanger.gz | |||
| SRR27871793_1.fastq.gz | Fastqsanger.gz | |||
| SRR27871793_2.fastq.gz | Fastqsanger.gz | |||
| SRR27871794_1.fastq.gz | Fastqsanger.gz |
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Project description:The phagocytic activity of astrocytes plays an important role in synapse refinement through the elimination of excess synapses during brain development. The adhesion G protein-coupled receptor BAI1/ADGRB1 contributes to phagocytosis in various tissues, including the clearance of apoptotic myoblasts in skeletal muscle and epithelial cells in the intestine. However, the phagocytic function of ADGRB1 in the brain has not been thoroughly investigated. Given that Adgrb1 is highly expressed in astrocytes but not in microglia, we examined changes in astrocyte gene expression resulting from the loss of ADGRB1. RNA-seq analysis revealed that astrocytes lacking ADGRB1 exhibit altered expression of genes associated with cytoskeleton organization and chemotaxis, processes that are required for phagocytosis. Using cultured astrocytes from mice lacking full-length ADGRB1 (Adgrb1exon2-/-) and wildtype (WT) littermates, we found that Adgrb1exon2-/- astrocytes exhibit significantly reduced phagocytic capacity when compared to similarly prepared astrocytes from WT littermates. Immunostaining of astrocytes and pre-synaptic markers showed less engulfed pre-synaptic elements in astrocytes from Adgrb1exon2-/- mutants. Finally, immunostaining of pre-synaptic and post synaptic markers revealed a significantly higher density of excitatory synapses in Adgrb1exon2-/- mutants. These findings highlight the importance of ADGRB1 in synaptic remodeling and raise the possibility that reduced astrocyte-mediated phagocytosis might underlie the behavioral alterations previously observed in Adgrb1exon2-/- mutants, including increased seizure susceptibility and deficits in social memory.
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Project description:Excitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses. After 10 days in culture, dissociated mouse hippocampal neurons in 6-well plates were infected with lentivirus expressing either Flag-Nr4a1 or GFP and incubated for 6 days to allow for transgene expression. Total RNA was then isolated using RNeasy Plus kit (QIAGEN). Samples passing an mRNA quality check proceeded to quantitative analysis on Agilent-026655 4x44 Mouse Microarrays.
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Project description:Cell surface receptors, including erythropoietin-producing hepatocellular A4 (EphA4), are important in regulating hippocampal synapse loss, which is the key driver of memory decline in Alzheimer’s disease (AD). However, the cellular-specific roles and mechanisms of EphA4 are unclear. Here, we show that EphA4 expression is elevated in hippocampal CA1 astrocytes in AD conditions. Specific knockout of astrocytic EphA4 ameliorates excitatory synapse loss in the hippocampus in AD transgenic mouse models. Single-nucleus RNA sequencing analysis revealed that EphA4 inhibition specifically decreases a reactive astrocyte subpopulation with enriched complement signaling, which are characteristics associated with synapse elimination by astrocytes in AD. Importantly, astrocytic EphA4 knockout in an AD transgenic mouse model decreases complement tagging on excitatory synapses and excitatory synapses within astrocytes. These findings suggest an important role of EphA4 in the astrocyte-mediated elimination of excitatory synapses in AD and highlight the crucial role of astrocytes in hippocampal synapse maintenance in AD.
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Project description:Homeostatic synaptic plasticity (HSP) is a fundamental neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating both of these processes are unknown. In this study, we investigate the role of miR-218-5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of miRNA-binding sites in differentially expressed genes changing upon PTX-induced HSD, we bioinformatically predicted and experimentally validated increased miR-218-5p activity upon PTX-treatment in the process compartment. By monitoring synapse structure in vitro with confocal microscopy, we demonstrate that miR-218-5p exerts a dual effect in HSD: it prevents the downscaling of excitatory synapses and dendritic spines, while at the same time blocking inhibitory synapse upscaling. Furthermore, we identify the Neuroligin2 interacting molecule Mdga1 as a crucial target of miR-218-5p in the context of homeostatic upscaling of inhibitory synapses. By performing long-term electroencephalographic (EEG) recordings, we further revealed that local inhibition of miR-218-5p in the somatosensory cortex reduced local slow-wave activity (SWA) during non-rapid-eye-movement (NREM) sleep. In summary, this study uncovers miR-218-5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity-induced perturbations, with potential implications for both physiological and pathological conditions.
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