Biology subjects

Ye, M.

Publications and source records attributed to Ye, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Karyotype Description and Comparative Chromosomal Mapping of 5S rDNA in 21 species

5S rDNA is essential component of all cell types. A survey was conducted to study the 5S rDNA site number, position, and origin of signal pattern diversity in 64 plants using fluorescence in situ hybridization. The species used for this experiment were chosen due to the discovery of karyotype rearrangement, and for species checked in which 5S rDNA has not yet been explored. The chromosome number was 14-160, while the chromosome length was 0.63-6.88 m, with 37 plants (58%) had small chromosome (<3 m). The chromosome numbers of three species and 5S rDNA loci of 19 species have been reported for the first time. 5S rDNA was varied and abundant in signal site number (2-18), position (e.g., interstitial, distal, and proximal position, occasionally, outside chromosome), and even as intense (e.g., strong, weak, and slight). Our results exposed modifiability in the number and location of 5S rDNA in 33 plants and demonstrated an extensive stable number and location of 5S rDNA in 31 plants. The potential origin of signal pattern diversity was probably caused by chromosome rearrangement (e.g., deletion, duplication, inversion, translocation), polyploidization, self-incompatibility, and chromosome satellites. These data characterized the variability of 5S rDNA within the karyotypes of the 64 plants that exhibited massive chromosomal rearrangements and provided anchor points for genetic physical maps. These data prove the utility of the 5S rDNA oligonucleotide as a chromosome marker in identifying plant chromosomes. This method provides a basis for developing similar applications for cytogenetic analysis in other species. Article SummaryA survey was exploited to study 5S rDNA signal pattern diversity in 64 plants by FISH. The chromosome number of three species and 5S rDNA loci of 19 species have been reported by the first time. 5S rDNA was really rather various and abundant in signal site number (2-18), position (interstitial, distal, proximal position, occasionally, outside chromosome), even as the intense (strong, week, slight). These data prove the utility of 5S rDNA oligonucleotide as chromosome marker in identifying plant chromosomes.

molecular biology↗

bioRxiv2024

CLSTN3B enhances adipocyte lipid droplet structure and function via endoplasmic reticulum contact

Interorganelle contacts facilitate material exchanges and sustain the structural and functional integrity of organelles. Lipid droplets (LDs) of adipocytes are responsible for energy storage and mobilization responding to body needs. LD biogenesis defects compromise the lipid-storing capacity of adipocytes, resulting in ectopic lipid deposition and metabolic disorders, yet how the uniquely large LDs in adipocytes attain structural and functional maturation is incompletely understood. Here we show that the mammalian adipocyte-specific protein CLSTN3B is crucial for adipocyte LD maturation. CLSTN3B employs an arginine-rich segment to promote extensive contact and hemifusion-like structure formation between the endoplasmic reticulum (ER) and LD, allowing ER-to-LD phospholipid diffusion during LD expansion. CLSTN3B ablation results in reduced LD surface phospholipid density, increased turnover of LD-surface proteins, and impaired LD functions. Our results establish the central role of CLSTN3B in the adipocyte-specific LD maturation pathway that enhances lipid storage and maintenance of metabolic health under caloric overload.

cell biology↗

bioRxiv2023

Mechanism of action of Buqing Granule against Diabetic retinopathy based on network pharmacology and animal experiments

ObjectiveFor this study, network pharmacology and animal experiments were used together to get a better idea of how BQKL works at the molecular level to treat DR. MethodsIn this study, we obtained the relevant action target information of BQKL from the TCMSP and also combined the GeneCards, OMIM, TTD, and PharmGKB databases with the GEO database to obtain the relevant target information of DR. The intersection of these targets was determined using a Venn diagram to identify the target of action for the treatment of DR with BQKL. The target proteins of BQKL for DR were then uploaded to the String database. The resultant data were imported into Cytoscape 3.9.0 to construct PPI networks and identify key targets of action. The DAVID database was used to do a GO and KEGG pathway enrichment analysis of target genes for treating DR with BQKL. Molecular docking was performed to validate the core action targets with the core compounds of BQKL. In addition, we induced DR production in rats by a high-fat, high-sugar diet and intraperitoneal injection of STZ and validated the results obtained from the network pharmacological analysis by changes in body weight and blood glucose, serum levels of biochemical markers, HE staining, immunohistochemistry, qRT-PCR, and Western blot experiments in rats. ResultsIn this study, quercetin, kaempferol, {beta}-sitosterol, lignanserin, and stigmasterol were identified as the key components, TP53, AKT1, JUN, CASPASE3, MAPK3, and MAPK1 as the key targets, and PI3K-Akt, AGE-RAGE, and MAPK signaling pathways as the main pathways involved. The results of animal experiments showed that BQKL could not only effectively reduce the degree of blood glucose, blood lipids, and oxidative damage in diabetic rats but also slow down the development process of DR. At the same time, it can significantly up-regulate the expression of AKT1, MAPK1, and MAPK3 and down-regulate the expression of CASPASE3, c-JUN, and TP53 in retinal tissue. ConclusionBQKL ameliorates oxidative stress, apoptosis, and inflammation due to hyperglycemia-related stress by regulating key targets of CASPASE3, AKT1, c-JUN, TP53, MAPK1, and MAPK3, thereby delaying the onset and progression of DR.

molecular biology↗

bioRxiv2023

uniLIVER: a Human Liver Cell Atlas for Data-Driven Cellular State Mapping

The liver performs several vital functions such as metabolism, toxin removal and glucose storage through the coordination of various cell types. The cell type compositions and cellular states undergo significant changes in abnormal conditions such as fatty liver, cirrhosis and liver cancer. As the recent breakthrough of the single-cell/single-nucleus RNA-seq (sc/snRNA-seq) techniques, there is a great opportunity to establish a reference cell map of liver at single cell resolution with transcriptome-wise features. In this study, we build a unified liver cell atlas uniLIVER by integrative analyzing a large-scale sc/snRNA-seq data collection of normal human liver with 331,125 cells and 79 samples from 6 datasets. Besides the hierarchical cell type annotations, uniLIVER also proposed a novel data-driven strategy to map any query dataset to the normal reference map by developing a machine learning based framework named LiverCT. Applying LiverCT on the datasets from multiple abnormal conditions (1,867,641 cells and 439 samples from 12 datasets), the alterations of cell type compositions and cellular states were systematically investigated in liver cancer.

bioinformatics↗

bioRxiv2023

Synapses are uniquely vulnerable to sleep loss during brain development while maturation confers resilience

Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long lasting changes in adult behavior. Different plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21-28), adolescent (P42-49) and adult (P70-100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition test. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of peri-neuronal nets. Our analysis further reveals the developing synapse as a convergent node between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing mechanistic insights for ASD susceptibility. Significance StatementSleep is a fundamental pillar of lifelong health. Sleep disruption is commonly associated with neurodevelopmental conditions including autism spectrum disorder (ASD) and schizophrenia. Therefore, understanding the vulnerabilities associated with developmental sleep loss is an essential research question. Here we systemically examine the molecular and behavioral consequence of sleep deprivation (SD) in developing and adult mice. Compared to adults, developing mice show absent or blunted adaptive responses to SD, and heightened sensitivity to SD-induced cognitive deficits. Our molecular analysis indicates sleep plays an important role in key aspects of brain development including synaptogenesis, and that the effects of SD converge on nodes of genetic risk for ASD. This study provides new insights into the role of sleep in healthy brain development.

neuroscience↗

bioRxiv2023

A peptide-centric local stability assay to unveil protein targets of diverse ligands

While tremendous progress has been made in chemical proteomics for identifying protein-ligand interactions, it remains challenging for proteome-wide identification of ligand-binding regions without modifying the ligands. Here, we discovered that "disruptive trypsinization" amplifies the readout of ligand-induced protein local stability shifts, and explored this notion in developing "peptide-centric local stability assay" (PELSA), a modification-free approach which achieves unprecedented sensitivity in proteome-wide target identification and binding-region determination. We demonstrate the versatility of PELSA by investigating the interactions across various biological contexts including drug-target interactions, metabolism, epitope mapping, metal proteomics, and post-translational modification recognition. A PELSA study of the oncometabolite R2HG revealed functional insights about its targets and pathogenic processes in both cancer and immune cells. Thus, beyond offering users unprecedented sensitivity for characterizing diverse target-ligand interactions, PELSA supports informative screening and hypothesis generation studies throughout life science.

biochemistry↗

bioRxiv2023

Taxonomical and ontological analysis of verified natural and laboratory human coronavirus hosts

To fully understand COVID-19, it is critical to identify and analyze all the possible hosts of SARS-CoV-2 (the pathogen of COVID-19) and compare them with the hosts of other human coronaviruses. In this study, we collected, annotated, and performed taxonomical and ontological analysis of all the reported and verified hosts for all human coronaviruses including SARS-CoV, MERS-CoV, SARS-CoV-2, and four others that cause the common cold. A total of 37 natural hosts and 19 laboratory animal hosts of host human coronaviruses were identified based on experimental or clinical evidence. Our taxonomical ontology-based analysis found that all the verified susceptible natural and laboratory animals belong to therian mammals. Specifically, these 37 natural therian hosts include one wildlife marsupial mammal (i.e., Didelphis virginiana) and 36 Eutheria mammals (a.k.a. placental mammals). The 19 laboratory animal hosts are also classified as placental mammals. While several non-therian animals (including snake, housefly, zebrafish) were reported to be likely SARS-CoV-2 hosts, our analysis excluded them due to the lack of convincing evidence. Genetically modified mouse models with human Angiotensin-converting enzyme 2 (ACE2) or dipeptidyl peptidase-4 (DPP4) protein were more susceptible to virulent human coronaviruses with clear symptoms. Coronaviruses often became more virulent and adaptive in the mouse hosts after a series of viral passages in the mice. To support knowledge standardization and analysis, we have also represented the annotated host knowledge in the Coronavirus Infectious Disease Ontology (CIDO) and provided ways to automatically query the knowledge.

bioinformatics↗

bioRxiv2023

Novel genetically encoded tools for imaging or silencing neuropeptide release from presynaptic terminals in vivo

Neurons produce and release neuropeptides to communicate with one another. Despite their profound impact on critical brain functions, circuit-based mechanisms of peptidergic transmission are poorly understood, primarily due to the lack of tools for monitoring and manipulating neuropeptide release in vivo. Here, we report the development of two genetically encoded tools for investigating peptidergic transmission in behaving mice: a genetically encoded large dense core vesicle (LDCV) sensor that detects the neuropeptides release presynaptically, and a genetically encoded silencer that specifically degrades neuropeptides inside the LDCV. Monitoring and silencing peptidergic and glutamatergic transmissions from presynaptic terminals using our newly developed tools and existing genetic tools, respectively, reveal that neuropeptides, not glutamate, are the primary transmitter in encoding unconditioned stimulus during Pavlovian threat learning. These results show that our sensor and silencer for peptidergic transmission are reliable tools to investigate neuropeptidergic systems in awake behaving animals.

neuroscience↗

bioRxiv2023

CircPLXNA2 affects the proliferation and apoptosis of myoblast through circPLXNA2/gga-miR-12207-5P/MDM4 axis

BackgroundcircRNAs are new-identified special endogenous RNA molecules that covalently close a loop by backsplicing with pre-mRNA. In the cytoplasm, circRNAs would act as molecular sponges to bind with specific miRNA to promote the expression of target genes. However, there is still in its fancy of knowing circRNA functional alternation in skeletal myogenesis. In this study, we favor a model to identify the circRNA-miRNA-mRNA interaction network in which the axis may be implicated in the progression of chicken primary myoblasts (CPMs) myogenesis by a combination of multi-omics (i.e., circRNA-seq and ribo-seq). ResultsIn total, 314 circRNA-miRNA-mRNA regulatory axis containing 66 circRNAs, 70 miRNAs, and 24 mRNAs that may be relevant to myogenesis were collected. With these, the circPLXNA2-gga-miR-12207-5P-MDM4 axis aroused our research interest. The circPLXNA2 is highly differentially expressed during differentiation versus proliferation. It was demonstrated that circPLXNA2 inhibited the process of apoptosis while at the same time stimulating cell proliferation. Furthermore, we demonstrated that circPLXNA2 could inhibit the repression of gga-miR-12207-5p to MDM4 by directing binding to gga-miR-12207-5p, thereby restoring MDM4 expression. ConclusionsCircPLXNA2 could function as a competing endogenous RNA (ceRNA) to inhibit the repression of gga-miR-12207-5p to MDM4 by directing binding to gga-miR-12207-5p, thereby recovering the expression of MDM4.

molecular biology↗

bioRxiv2022

Superiority of intranasal over systemic administration of bioengineered soluble ACE2 for survival and brain protection against SARS-CoV-2 infection

The present study was designed to investigate the effects of a soluble ACE2 protein termed ACE2 618-DDC-ABD, bioengineered to have long duration of action and high binding affinity to SARS-CoV-2, when administered either intranasally (IN) or intraperitoneally (IP) and before or after SARS-CoV-2 inoculation. K18hACE2 mice permissive for SARS-CoV-2 infection were inoculated with 2x104 PFU wildtype SARS-CoV-2. In one protocol, ACE2 618-DDC-ABD was given either IN or IP, pre- and post-viral inoculation. In a second protocol, ACE2 618-DDC-ABD was given either IN, IP or IN+IP but only post-viral inoculation. In addition, A549 and Vero E6 cells were used to test neutralization of SARS-CoV-2 variants by ACE2 618-DDC-ABD at different concentrations. Survival by day 5 was 0% in infected untreated mice, and 40% in mice from the ACE2 618-DDC-ABD IP-pre treated group. By contrast, in the IN-pre group survival was 90%, histopathology of brain and kidney was essentially normal and markedly improved in the lungs. When ACE2 618-DDC-ABD was administered only post viral inoculation, survival was 30% in the IN+IP group, 20% in the IN and 0% in the IP group. Brain SARS-CoV-2 titers were high in all groups except for the IN-pre group where titers were undetectable in all mice. In cells permissive for SARS-CoV-2 infection, ACE2 618-DDC-ABD neutralized wildtype SARS-CoV-2 at high concentrations, whereas much lower concentrations neutralized omicron BA. 1. We conclude that ACE2 618-DDC-ABD provides much better survival and organ protection when administered intranasally than when given systemically or after viral inoculation and that lowering brain titers is a critical determinant of survival and organ protection.

pathology↗

bioRxiv2022

Gluebodies improve crystal reliability and diversity through transferable nanobody mutations that introduce constitutive crystal contacts

The design of proteins that may assemble in a manner that is transferable and modular remains an enduring challenge. In particular, obtaining well-diffracting protein crystals suitable for characterizing ligands or drug candidates and understanding different protein conformations remains a bottleneck for structural studies. Using nanobodies as crystallization chaperones is one strategy to address the problem, but its reliability is uncharacterized and, in this study, we observed it to have a limited success rate. Here we show that by exploring and testing the nanobody-nanobody interfaces predominant in >200 combinations of surface mutations in multiple iterations we can engineer robust crystallization behaviour into the nanobody scaffold. Strikingly, this survey yielded multiple polymorphs, all mediated by the same interface. The resulting Gluebodies (Gbs) provide far superior resolution and reliability of diffraction and can be routinely generated for chaperone experiments. We furthermore show that Gbs cannot rescue intrinsically non-crystallizing proteins, but instead are a powerful approach to improve the packing and resolution limit of poorly diffracting crystals. The discovery of an engineered, preferred nanobody interface that arises under kinetic control - trapped here by irreversible crystallization - embodies a protein assembly strategy that could prove even more broadly useful for modular assembly trapped by other irreversible methods.

biochemistry↗

bioRxiv2022

Regional and cell type-specific afferent and efferent projections of the mouse claustrum

The claustrum (CLA) is a conspicuous subcortical structure interconnected with cortical and subcortical regions. However, its regional anatomy and cell-type-specific connections in the mouse remain largely undetermined. Here, we accurately delineated the boundary of the mouse CLA and quantitatively investigated its inputs and outputs brain-wide using anterograde and retrograde viral tracing and fully reconstructed single claustral principal neurons. At a population level, the CLA reciprocally connects with all isocortical modules. It also receives inputs from at least 35 subcortical structures but sends projections back to only a few of them. We found that cell types projecting to the CLA are differentiated by cortical areas and layers. We classified single CLA principal neurons into at least 9 cell types that innervate the diverse sets of functionally linked cortical targets. Axons of interneurons within the CLA arborize along almost its entire anteroposterior extent. Together, this detailed wiring diagram of the cell-type-specific connections of the mouse CLA lays a foundation for studying its functions.

neuroscience↗

bioRxiv2021

PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. Its depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. The enzymatic activity of PRMT1 is also required to stimulate the canonical Wnt pathway. Recently developed type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients, as well as the EGFR inhibitor, erlotinib. Therefore, targeting PRMT1 in combination with drugs used in the clinic may improve current treatments for TNBC patients. SignificanceThis study highlights the requirement of PRMT1 for breast cancer cell survival and demonstrates the potential of targeting type I PRMTs in combination with chemotherapies in triple-negative breast cancer.

cancer biology↗

bioRxiv2021

Induction of transposable element expression is central to innate sensing

Evidence indicates that transposable elements (TEs) stimulate innate sensing pathways in various pathologies but it is not clear whether they are sensed during normal physiological responses. Here we show that, during activation with an exogenous pathogen associated molecular pattern (PAMP), dendritic cells (DCs) epigenetically remodel heterochromatin at TEs by depleting the methyltransferase Suv39h1 and reducing histone-3 lysine-9 trimethylation (H3K9me3). TLR4 signaling activates TE expression to enhance innate responses through the DNA sensor cGAS. Cytosolic cGAS-bound DNA comprised LINE1 TEs as the predominant endogenous ligands. Concordantly, LINE1 inhibition attenuated the type-I IFN response to LPS and rescued influenza virus infection. We propose that in healthy cells, exogenous PAMPs epigenetically activate self-derived PAMPs (LINE1) that engage cGAS to enhance responses. These data explain why pathogens employ redundant and broad innate immune countermeasures, to suppress activation of host PAMPs and illustrate a hitherto unappreciated role for host genome-derived PAMPs in response to pathogens.

immunology↗

bioRxiv2021

Constructing a warhead of PROTAC with aptamer for tumor-selective degradation of nucleolin

PROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, most PROTACs generated lack cell-type selectivity and have poorly soluble in water. To address this drawback, we developed a novel PROTAC ZL216 using aptamer AS1411 as a targeting ligand of nucleolin to conjugate with a small molecule ligand of E3 ligase VHL, which shows high aqueous solubility and serum stability. Based on the differential expression of nucleolin on the cell surface, ZL216 could bind to and internalize into breast cancer cells, but not normal breast cells. Furthermore, we revealed that ZL216 promoted the formation of a nucleolin-ZL216-VHL ternary complex in breast cancer cells and potently induced nucleolin degradation in vitro and in vivo. As a result, ZL216 inhibited the proliferation and migration of breast cancer cells. These studies demonstrate that in addition to peptides and small molecule compounds, nuclei acid aptamers can also be used to generate PROTACs, which broadens the toolbox constructing PROTACs and provides a promising strategy for development of tumor-selective PROTACs.

biochemistry↗

bioRxiv2021

A human ensemble cell atlas (hECA) enables in data cell sorting

Single-cell omics data can characterize multifaceted features of massive cells and bring significant insights to biomedical researches. The accumulation of single-cell data provides growing resources for constructing atlases for all cells of a human organ or the whole body. The true assembly of a cell atlas should be cell-centric rather than file-centric. We proposed a unified information framework enabling seamless cell-centric data assembly and developed a human Ensemble Cell Atlas (hECA) as an instance. hECA version 1.0 assembled scRNA-seq data across multiple studies into one orchestrated data repository. It contains 1,093,299 labeled cells and metadata from 116 published human single-cell studies, covering 38 human organs and 11 systems. We invented three methods of applications based on the cell-centric assembly: "In data" cell sorting enables targeted data retrieval in the full atlas with customizable logic expressions; The "quantitative portraiture" system provides a multi-view presentation of biological entities (organs, cell types, and genes) of multiple granularities; The customizable reference creation allows users to use the cell-centric assembly to generate references for their own cell type annotations. Case studies on agile construction of user-defined sub-atlases and "in data" investigation of CAR-T off-targets in multiple organs showed the great potential of cell-centric atlas assembly.

bioinformatics↗

bioRxiv2021

gcaPDA: A Haplotype-resolved Diploid Assembler

Generating chromosome-scale haplotype resolved assembly is important for functional studies. However, current de novo assemblers are either haploid assemblers that discard allelic information, or diploid assemblers that can only tackle genomes of low complexity. Here, we report a diploid assembler, gcaPDA (gamete cells assisted Phased Diploid Assembler), which exploits haploid gamete cells to assist in resolving haplotypes. We generate chromosome-scale phased diploid assemblies for the highly heterozygous and repetitive genome of a maize F1 hybrid using gcaPDA and evaluate the assembly result thoroughly. With applicability of coping with complex genomes and fewer restrictions on application than other diploid assemblers, gcaPDA is likely to find broad applications in studies of eukaryotic genomes.

genomics↗

bioRxiv2021

Coordinated regulation of CB1 cannabinoid receptors and anandamide metabolism stabilize network activity during homeostatic scaling down

Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the post-synaptic compartments to regulate synaptic transmission, plasticity, and neuronal excitability primarily through retrograde activation of pre- synaptic cannabinoid receptor type 1 (CB1). The eCB system is well-situated to regulate neuronal network properties and coordinate pre- and post-synaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. To address this issue, we used western blot and targeted lipidomics to measure adaptations in eCB system to bicuculline (BCC)-induced chronic hyperexcitation in mature (>DIV21) cultured rat cortical neurons, and used multielectrode array recording and live-cell imaging of glutamate dynamics to test the effects of pharmacological manipulations of eCB on network activities. We show that BCC-induced chronic hyperexcitation triggers homeostatic downscaling and a coordinated adaptation to enhance tonic eCB signaling. Hyperexcitation triggers first the downregulation of fatty acid amide hydrolase (FAAH), the lipase that degrades the eCB anandamide, then an accumulation of anandamide and related metabolites, and finally a delayed upregulation of surface and total CB1. Additionally, we show that BCC-induced downregulation of surface AMPA-type glutamate receptors (AMPARs) and upregulation of CB1 occur through independent mechanisms. Finally, we show that endocannabinoids support baseline network activities before and after downscaling and is engaged to suppress network activities during adaptation to hyperexcitation. We discuss the implications of our findings in the context of downscaling and homeostatic regulation of oscillatory network activities. Significance statementNeurons are remarkably resilient to perturbations in network activities thanks to the expression of overlapping homeostatic adaptations. In response to network hyperactivity or silencing, neurons respond through regulating excitatory and inhibitory post-synaptic neurotransmitter receptors density, probability of pre-synaptic neurotransmitter release, and/or membrane excitability. The endocannabinoid system is a prominent signaling pathway at many synapses that is known to be involved in multiple forms of short- and long-term synaptic plasticity. Here we find that components of the endocannabinoid system are upregulated in response to chronic hyperexcitation of cultured cortical neurons, and that endocannabinoid signaling is required to maintain network activity but also suppresses network events during hyperexcitation. This work supports a novel tonic homeostatic function for the endocannabinoid system in neurons.

neuroscience↗