Biology subjects

Takeuchi, H.

Publications and source records attributed to Takeuchi, H..

At least 19 recordsLinked to original sources

bioRxiv2026

EC1 body controls sperm cell reception via gamete pit formation.

The remarkable efficiency of double fertilization in flowering plants depends on the precise delivery of immotile sperm cells to two female gametes1. Although sperm cells are rapidly released from the pollen tube, how they are accurately directed to their fertilization site has remained unknown. Here we identify a transient extracellular structure, termed the gamete pit, that forms at the egg cell-central cell (EC-CC) interface immediately after pollen tube discharge and serves as the landing site for sperm cells. Gamete pit formation is enabled by localized dissociation of the EC-CC interface, mediated by extracellular protein assemblies designated EC1 bodies. These structures contain extracellular deposits enriched in EGG CELL 1 (EC1) peptides2, including amyloid-like assemblies. Loss of EC1 bodies prevented gamete pit formation, causing sperm-cell backflow or catastrophic over-penetration of pollen tube contents into the central cell. Surprisingly, ectopic deposition of a heterologous amyloidogenic protein alleviated over-penetration and partially restored fertility. Our findings reveal a mechanism by which extracellular protein assemblies remodel the gamete interface for sperm-cell reception, uncover an unexpected structural role for the conserved gamete-activating peptide EC1, and establish protein-mediated cell-interface remodeling as a fundamental principle underlying double fertilization in flowering plants.

plant biology↗

bioRxiv2026

CRISPR activation screens identify core protein-dependent regulation of heparan sulfate sulfation and ligand specificity

Heparan sulfate proteoglycans (HSPGs) are essential cell surface and extracellular matrix glycoconjugates that mediate diverse biological processes through interactions between their heparan sulfate (HS) chains and extracellular ligands. While HS sulfation patterning is known to dictate ligand specificity, how cells control HS assembly to regulate these interactions remains incompletely understood. To systematically identify genetic modifiers of HS-protein interactions, we performed genome-wide CRISPR activation (CRISPRa) screens in HEK293T cells using binding of antithrombin (AT), which selectively recognizes 3-O-sulfated HS motifs, or the N-sulfation-specific antibody 10E4 as functional readouts. Strikingly, the screens revealed proteoglycan core proteins as key modulators of HS function. In particular, syndecan-1 (SDC1) emerged as a preferential enhancer of AT binding compared to other syndecan family members. Targeted upregulation of syndecan family members increased total HS levels, but only SDC1 enhanced AT binding. Structural and enzymatic analyses demonstrated that SDC1-associated HS chains contain elevated 6-O-sulfation and serve as superior substrates for 3-O-sulfotransferases relative to SDC2-associated HS chains. Additionally, SDC1 exhibited slower cell surface recovery, which was blocked by cycloheximide treatment, consistent with extended trafficking and biosynthetic processing. Overall, these findings indicate that proteoglycan core protein identity influences HS sulfation patterning and ligand-binding specificity and trafficking kinetics may contribute to core protein-dependent regulation of HS modification.

Cell Biology↗

bioRxiv2026

Minimally invasive measurement of maternal transcripts enables predicting the developmental potential of mammalian zygotes

Maternal transcripts are stored in the oocyte cytoplasm during oogenesis and play a pivotal role in early embryonic development after fertilization. However, specific maternal transcripts that reflect the developmental potential of embryos have not been systematically identified, and the use of maternal transcript levels as an indicator of successful development has not been explored. Here, we link the maternal transcriptome to the zygotes developmental potential by examining transcripts in a single polar body. The transcriptome of a zygote or an oocyte was highly similar to that of its accompanying polar body in mouse, cow, and human. We have identified a set of maternal transcripts whose expression levels fluctuate between poor- and good-quality zygotes. Specifically, Sipa1and Zmym6 were identified as marker transcripts that accurately reflect the developmental potential of zygotes. Using these marker genes, combined with machine learning, the development of zygotes to the blastocyst stage was successfully predicted with more than 80% specificity as early as 12 hours after fertilization. Furthermore, our prediction platform significantly improved implantation rates and live births to term. Thus, we have demonstrated a minimally invasive method for identifying maternal transcripts associated with zygote developmental potential. Our developed prediction system provides a generalizable conceptual framework for human infertility treatment to reduce the risk of implantation failure by excluding embryos with low developmental potential, especially when early embryos are transferred, and for livestock propagation to assess selected expressed maternal trait-associated variants before embryo transfer.

developmental biology↗

bioRxiv2026

Oxytocin regulates TN-GnRH3 circuit maturation and mate preference through C1q-dependent synaptic mechanisms

Oxytocin is a key regulator of social behavior, yet how it shapes the neural circuits underlying these behaviors remains unclear. Here, we show that oxytocin signaling is required for the proper maturation of terminal nerve gonadotropin-releasing hormone 3 (TN-GnRH3) circuits that regulate female mate preference in medaka. Disruption of oxytocin signaling reduced expression of the complement component C1q, altered microglial properties, and increased TN-GnRH3 innervation in the optic tectum and dorsolateral telencephalon, suggesting impaired synaptic refinement. In addition, TN-GnRH3 neurons in mutants exhibited disrupted clustering and failed to increase firing frequency in response to visual stimulation, indicating functional deficits. Furthermore, c1qb mutants phenocopied the behavioral and neuronal abnormalities observed in oxytocin signaling-deficient mutants. Together, our findings suggest that oxytocin signaling links microglia-associated synaptic refinement to neural circuit maturation, thereby revealing a previously unrecognized role for oxytocin in shaping social behavior.

neuroscience↗

bioRxiv2025

Identification of a novel small molecule facilitating HIV elimination by the "Shock-and-Kill" approach

The development of antiretroviral therapy (ART) has significantly improved the prognosis of people living with HIV (PLWH). However, reservoirs of latent viruses represent a major barrier to achieving a complete cure of HIV infection. To overcome the burden of viral latency, the "Shock-and-Kill" strategy employs latency-reversing agents (LRAs) to reactivate the virus and thus render it susceptible to elimination. Existing LRAs are not optimal and there is an unmet need for improvement. By screening a small molecule library, we identified the novel LRA candidate 2-HSB (2-hydrido-2,2-spirobi(1,3,2-benzodioxaphosphole)) which not only reactivates latent HIV provirus but also induces specific cytopathic effects in both monocytic and T lymphocytic latent HIV reservoirs. Thus, this novel compound represents a dual "shock and kill" agent, unlike known LRAs which are limited to the "shock". The probable involvement of HIV-1 tat protein may account for its selectivity. Although both shock and kill effects seemed to be regulated by spleen tyrosine kinase, they were independent of each other, indicating that neither activation-induced cell death nor cell death-induced reactivation was occurring. Crucially, 2-HSB induced viral transcription in ART-suppressed PLWH samples in vitro. Our findings present 2-HSB as a promising dual-action compound for the "Shock and Kill" strategy, demonstrating efficacy in both transformed cell lines and clinically-relevant primary samples. These results raise the possibility of distinguishing the mode of action of the two effects, potentially leading to the development of a single agent causing both HIV-1 reactivation and elimination and contributing to the improvement of treatment.

microbiology↗

bioRxiv2025

Pseudovirus-Mediated Proximity Labeling Identifies Candidate Host Cell Membrane Proteins Involved in Viral Attachment

Viral infections represent a significant threat to humanity, as exemplified by the COVID-19 pandemic. To mitigate the associated damage, it is essential to understand the biological characteristics of causative viruses. In this study, we report a novel method for identifying host cell molecules (including virus receptor) required for viral attachment, referred to here as "Host Cell Attachment Factors (HCAFs)". Our approach utilizes proximity labeling (PL) technology: pseudoviruses engineered to express a PL enzyme are applied to host cells, where they bind and initiate proximity labeling. Since HCAFs are expected to be localized near viral attachment sites, candidate HCAFs are specifically tagged by the PL process. Analysis of influenza HCAFs enabled the identification of multiple candidate molecules. Subsequent virus attachment experiments using CHO cells suggested that NRP1 may serve as an HCAF for influenza viruses. Given its simplicity and rapid turnaround, this method is adaptable to a wide range of enveloped viruses, including pandemic viruses that require emergency analysis.

microbiology↗

bioRxiv2025

Age-Dependent, Odorant-Specific Changes in Olfactory Sensitivity in an Alzheimer's Disease Mouse Model

BackgroundOlfactory impairment often precedes cognitive decline in Alzheimers disease (AD). Recent studies suggest odor specificity in olfactory deficits during early AD stages, making olfactory tests a promising tool for early diagnosis. However, the mechanisms underlying olfactory impairment remain unclear, complicating the identification of optimal odorants for diagnostic purposes. ObjectiveIn this study, we assessed olfactory sensitivity in a knock-in mouse model of Alzheimers disease (AppNL-G-F mice) that recapitulates key features of human AD pathology. MethodsTo evaluate odor detection thresholds, we employed an olfactory assay that leverages innate behavior without requiring associative learning. Six odorants representing distinct functional groups were tested in wild-type (WT) and AppNL-G-F mice at 2 and 4 months of age. ResultsAppNL-G-F mice exhibited odorant-specific hyposmia at 4 months of age, coinciding with amyloid deposition in cortical and subcortical regions but preceding measurable cognitive deficits. Unexpectedly, at an earlier stage (2 months), these mice showed odorant-specific hyperosmia to ester odorants, which transitioned to hyposmia by 4 months, indicating dynamic, age-dependent alterations in olfactory sensitivity as AD pathology progresses. ConclusionsOur findings demonstrate that odorant-specific olfactory testing could serve as a promising diagnostic tool for early-stage AD, providing insights into the mechanisms underlying olfactory dysfunction in neurodegenerative diseases.

pathology↗

bioRxiv2025

Establishment of a transgenic strain for the whole brain calcium imaging in larval medaka fish (Oryzias latipes)

GCaMP-based calcium imaging is a powerful tool for investigating neural function in specific neurons. We generated transgenic (Tg) medaka strains expressing jGCaMP7s across extensive brain regions under the control of the gap43 promoter. Using these Tg larvae, calcium imaging successfully detected a tricaine-induced suppression of spontaneous neural activity and topographical visual responses in the optic tectum elicited by moving paramecia or optical fiber stimulation. These results indicate that our Tg medaka strains provide a versatile platform for investigating neural dynamics and their responses to various stimuli.

molecular biology↗

bioRxiv2025

Differential O-Glc elongation on the specific EGF repeat within a ligand binding domain regulates NOTCH1 signaling

Three types of O-linked glycosylation - O-glucose, O-fucose, and O-N-acetylglucosamine - are crucial for the function of Notch receptors, which regulates critical cell fate determination processes in a wide variety of contexts. O-Glucose glycans are added to serine residues located between the first and second conserved cysteines within the epidermal growth factor (EGF) -like repeats in the Notch extracellular domain. Previously, O-glucose glycans were shown to be extended to a trisaccharide structure with two xyloses via an 1-3 linkage. Our recent studies, however, indicated that the O-glucose glycan on NOTCH1 EGF10 can be extended by hexose and Neu5Ac. Here, we demonstrated that this hexose- and Neu5Ac-extended glycan has a 3-sialyllactose-like structure synthesized by specific members of two isoenzyme families, B4GALT1 and ST3GAL4. Using mass spectrometry, we identified this modification exclusively on NOTCH1 EGF10 and NOTCH3 EGF9 (equivalent to NOTCH1 EGF10), with no detection in any other EGF domains in NOTCH1-3. Sequence comparison and mutagenesis experiments identified one amino acid at position -2 of the fourth cysteine in the EGF domain as crucial for the galactose elongation of O-glucose glycans. We further demonstrated that this site-specific elongation of O-glucose on NOTCH1 EGF10 significantly impact ligand binding and signal transduction of NOTCH1. Our findings contribute to the understanding of the intricate regulatory mechanisms of Notch receptor function mediated by distinct positions and structures of O-glycans. Significance StatementNotch, a signaling receptor critical for development, differentiation, and homeostasis in multicellular organisms, undergoes multiple post-translational glycan modifications to regulate its function. While O-glucose glycan elongation by xylose was previously known, we identified an O-glucose glycan extended by galactose and Neu5Ac on specific epidermal growth factor (EGF) -like repeats of certain Notch paralogs, NOTCH1 and NOTCH3. As far as we know, this structure has not been reported on any other proteins. We identify the enzymes involved in the biosynthesis of this glycan and demonstrate that modifications at a specific site on Notch direct receptor functions, including ligand binding and Notch signaling.

biochemistry↗

bioRxiv2024

Microthrombi-growth in ADAMTS13 deficiency exacerbated ulcerative colitis via mucosal and endothelial dysfunction

BackgroundUlcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation and ulceration, with systemic immune dysregulation exacerbating disease progression. While the accumulation of von Willebrand factor (VWF), normally digested by a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13) from ultra-large multimers to small molecules, has been implicated in UC pathogenesis, the association between aberrant microthrombus formation and colitis remains unclear. MethodsPlasma and inflamed colonic tissues from UC patients were analyzed. In the experimental colitis model, we employed an intravital imaging technique to reveal real-time structural dynamics of the mucus layer and the mucosal vasculature. Dextran sulfate sodium (DSS)-induced colitis in wild-type and ADAMTS13-deficient mice was evaluated for disease progression, mucus layer disruption, leukocyte recruitment, and thrombus formation in mucosal vessels using intravital multiphoton excitation microscopy within single-cell spatial resolution. ResultsUC patients exhibited significantly reduced plasma ADAMTS13 activity correlating with disease severity and excessive VWF deposition in inflamed colonic tissues. In DSS-induced colitis mice, ADAMTS13 deficiency showed heightened disease activity and increased mucosal erosion in histochemical analysis compared to wild-type mice. A novel methodology established in this study using intravital microscopy successfully appraised colonic mucus barrier integrity by visualizing fluorescent dextran penetration from the colonic lumen to the crypts. ADAMTS13 deficiency accelerated mucus layer disruption, leukocyte adhesion, and microthrombi formation, particularly close to crypt epithelium regions. Vessel-specific analyses demonstrated that obstructive microthrombi were most prominent in the mucosal layer, contributing to local ischemia and mucosal erosion. Therapeutical usage of recombinant human ADAMTS13 alleviated microthrombus formation, improved mucosal integrity, and mitigated colitis severity in wild-type and ADAMTS13-deficient mice. ConclusionsObstructive thrombi formed in mucosal vessels due to impaired ADAMTS13 activity appeared essential in the disease progression of UC. Advanced intravital imaging provided novel insights into single-cell resolution UC pathogenesis.

physiology↗

bioRxiv2024

Retention of DLK1 in the endoplasmic reticulum identifies roles for EGF domain-specific O-glycans in the secretory pathway

In the endoplasmic reticulum (ER), O-glycosylation by O-fucose, O-glucose, and O-GlcNAc occurs in the epidermal growth factor-like (EGF) domains of secreted or transmembrane glycoproteins. Previous studies focusing on Notch receptors have revealed the pivotal role of these O-glycans in the cell surface expression of Notch or secretion of truncated Notch fragments. Although it has been demonstrated that O-fucose, O-glucose, and O-GlcNAc stabilize individual EGF domains, their role in the secretory pathway after the completion of the folding process remains unexplored. In this study, we used delta-like 1 homolog (DLK1) containing six consecutive EGF domains as a model glycoprotein to investigate the role of EGF domain-specific O-glycans in the secretory pathway. Semi-quantitative site-specific glycoproteomics of recombinantly expressed DLK1 revealed multiple O-fucose and O-glucose modifications in addition to an unusual EOGT-dependent O-hexose modification. Consistent with the results of the secretion assay, inactivation of the glycosyltransferases modifying O-fucose and O-glucose, but not the newly identified O-hexose, perturbed the transport of DLK1 from the ER during retention using the selective hooks (RUSH) system. Importantly, the absence of O-fucose did not result in an apparent loss of O-glucose modification within the same EGF domain, and vice versa. Given that protein O-fucosyltransferase 1 and protein O-glucosyltransferase 1 activities depend on the folded state of the EGF domains, O-glycans affected DLK1 transport independently of the folding process required for O-glycosylation in the ER. These findings highlight the distinct roles of O-glycans in facilitating the transport of DLK1 from the ER to the cell surface.

biochemistry↗

bioRxiv2024

Host-encoded DNA methyltransferases modify the epigenome and host tropism of invading phages

Restriction modification (RM) systems are ubiquitous bacterial defense systems; however, some phages evade RM system and adapt to their bacterial hosts. In such cases, phages are thought to stochastically acquire DNA methylation from host-encoded DNA methyltransferases (MTases), facilitating host adaptation. However, no studies have directly compared the methylomes of host bacteria and their infecting phages. Here, we demonstrate the epigenetic landscape of adapted phages with diverse infection histories, focusing on the broad host-range phage KHP30T as its adapts to three Helicobacter pylori strains. Using a multistage infection system, we observed that the adapted phages displayed significantly high titers against the last infected H. pylori strain, suggesting an attendant change in host tropism. Single-molecule real-time sequencing revealed that methylated motifs were predominantly shared between the adapted phages and their most recent host. Our findings enhance our understanding of epigenetic phage-host interactions, which have significant implications for microbial ecology.

microbiology↗

bioRxiv2024

Development of a Versatile System to Facilitate Targeted Knockout/Elimination Using CRISPR/Cas9 for Highly Duplicated Gene Families in Arabidopsis Sexual Reproduction

CRISPR/Cas9-based targeted gene editing is a fundamental technique for studying gene functions in various organisms. In plants, the introduction of a T-DNA construct harboring Cas9 nuclease and single guide RNA (sgRNA) sequences induces sequence-specific DNA double-strand breaks, inducing the loss of gene function. Arabidopsis thaliana is a model for CRISPR/Cas9 system development and gene function studies; the introduction of Cas9 under the egg or zygote promoter and multiple sgRNA modules generates heritable or non-mosaic mutants for multiple targets in the T1 generation of A. thaliana. Recent reports reflect use of several CRISPR/Cas9 vectors in generating single- and higher-order mutants; however, the development of a reliable, cost-effective, and high-throughput CRISPR/Cas9 platform is necessary for targeting highly duplicated gene families. In this study, we have developed a simple and user-friendly construction system for the CRISPR/Cas9 vector series with improved gene editing efficiency by simply inserting a single intron into Cas9, and effectively demonstrated the simultaneous knockout of multiple genes involved in A. thaliana sexual reproduction. An unbiased PCR-mediated mutant identification in the T1 generation revealed that our CRISPR/Cas9 system can support a > 70 kb deletion of > 30 tandemly duplicated synergid-specific genes and simultaneous knockout of five redundant genes essential for double fertilization. We performed a one-shot knockout of seven homologous pollen tube receptor-like kinase genes and identified their specific and overlapping roles in pollen tube growth and guidance. Our system can potentially facilitate further research in experimental plant biology to search for genetically unidentified components using reverse genetic candidate approaches.

plant biology↗

bioRxiv2023

Rapid body colouration change in Oryzias celebensisas a social signal for intraspecific competition

In some species, such as chameleon and cichlid fish, rapid body colouration changes (within seconds or minutes) serve as visual social signals in male-male competition. This study investigated the relationship between aggressive behaviour and body colouration changes in Oryzias celebensis, an Indonesian medaka fish. We analysed aggressive behaviours and corresponding body colouration changes during attack events in a controlled laboratory setting using groups of 3 adult fish in a small tank. In a triadic relationship consisting of 2 males and a female, males with blackened markings attacked more frequently than males without blackened markings and females. Additionally, we observed that the males with blackened markings were seldom attacked by males without blackened markings and females. These tendencies persisted even in groups consisting of 3 males. Our results suggest that the blackened markings in male O. celebensis not only indicate the level of aggression but also serve as a social signal to suppress attacks by other individuals.

animal behavior and cognition↗

bioRxiv2023

Transcriptomic landscape of seedstick in Arabidopsis thaliana funiculus after fertilisation

In Angiosperms, the continuation of plant species is intricately dependent on the funiculus multifaceted role in nutrient transport, mechanical support, and dehiscence of seeds. SEEDSTICK (STK) is a MADS-box transcription factor involved in seed size and dehiscence, and one of the few genes identified as affecting funiculus growth. Given the importance of the funiculus to a correct seed development, allied with previous phenotypic observations of stk mutants, we performed a transcriptomic analysis of stk funiculi, using RNA-sequencing, to infer on the deregulated networks of genes. The generated dataset of differentially expressed genes was enriched with cell wall biogenesis, cell cycle, sugar metabolism and transport terms, all in accordance with stk phenotype. We selected eight differentially expressed genes involved with abscission, seed development or novel functions in stk funiculus, such as hormones/secondary metabolites transport, for transcriptome validation using qPCR and/or promoter reporter lines. Overall, the analysis performed in this study allowed delving into the STK-network established in Arabidopsis funiculus, fulfilling a literature gap. Simultaneously, our findings reinforced the reliability of the transcriptome, and identified processes and new candidate genes that will enable a better understanding on the role of this sporophytic structure and how seed development may be affected by it.

plant biology↗

bioRxiv2023

The Chaperone NASP Contributes to De Novo Deposition of the Centromeric Histone Variant CENH3 in Arabidopsis Early Embryogenesis

The centromere is an essential chromosome region where the kinetochore is formed to control equal chromosome distribution during cell division. The centromere-specific histone H3 variant CENH3 (also called CENP-A) is a prerequisite for the kinetochore formation. Since CENH3 evolves rapidly, associated factors, including histone chaperones mediating the deposition of CENH3 on the centromere, are thought to act through species-specific amino-acid sequences. The functions and interaction networks of CENH3 and histone chaperons have been well-characterized in animals and yeasts. However, molecular mechanisms involved in recognition and deposition of CENH3 are still unclear in plants. Here, we used a swapping strategy between domains of CENH3 of Arabidopsis thaliana and the liverwort Marchantia polymorpha to identify specific regions of CENH3 involved in targeting the centromeres and interacting with the general histone H3 chaperone, NASP (nuclear autoantigenic sperm protein). CENH3s LoopN-1 region was necessary and sufficient for the centromere targeting in cooperation with the 2 region and was involved in interaction with NASP in cooperation with N, suggesting a species-specific CENH3 recognition. In addition, by generating an Arabidopsis nasp knockout mutant in the background of a fully fertile GFP-CENH3/cenh3-1 line, we found that NASP was implicated for de novo CENH3 deposition after fertilization and thus for early embryo development. Our results imply that the NASP mediates the supply of CENH3 in the context of the rapidly evolving centromere identity in land plants.

plant biology↗

bioRxiv2023

HIV-Tocky system to visualize proviral expression dynamics

The stably integrated pool of HIV-1 proviruses in the host genome stands against curative strategies. This reservoir is extremely heterogeneous with respect to host cell type, anatomical location, integration site, and replication fitness. During the initial phase of infection, only a few infected cells can resist host immune clearance or cytopathic effect and establish this resistant pool. The mechanisms underlying HIV latency initiation are not fully resolved yet. In the current study, we propose and validate a new reporter model for monitoring HIV-1 provirus silencing and reactivation using Timer of cell kinetics and activity (Tocky). HIV-Tocky system uses a fluorescent Timer protein whose emission spectrum spontaneously shifts from blue to red to reveal HIV-1 provirus dynamics. We dissected provirus transcriptional phases into early, persistent, recently silenced, and latent. To our knowledge, this is the first report to distinguish two latent subsets: a directly non-expressing population and a recently silenced after brief expression. In-depth integration site analysis suggested that the distribution of proviruses in directly latent cells was similar to that in actively transcribing cell population, whereas recently silenced cells tended to harbor proviruses integrated into heterochromatin. Furthermore, we established a library of various single integration clones at which we utilized to demonstrate the efficiency of the block-and-lock strategy by capturing the fast dynamics of silencing that were overlooked in previous models. In summary, we propose HIV-Tocky system to serve as a time-sensitive model that can capture the dynamics of provirus expression, making it a useful tool for HIV latency research. Significance StatementDeterminants of HIV-1 latency establishment are yet to be elucidated. This reservoir comprises a rare fraction of infected cells that can survive host and virus-mediated killing. In vitro reporter models so far offered a feasible means to inspect this population, but with limited capabilities to dissect provirus silencing dynamics. Here, we describe a new HIV reporter model (HIV-Tocky) with dual fluorescence spontaneous shifting to reveal provirus silencing and reactivation dynamics. This unique feature allowed; for the first time, identifying two latent populations: a directly latent, and a recently silenced subset, with the latter having integration features suggestive of stable latency. Our proposed model can help address the heterogeneous nature of HIV reservoirs and offers new possibilities for evaluating eradication strategies. ClassificationBiological Sciences, Microbiology.

microbiology↗

bioRxiv2023

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist, L-DOPA, to treat Parkinsons disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we searched for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identified the enlarged axon terminals of striatal medium spiny neurons in both LID and TD model mice. The striatal overexpression of vesicular gamma-aminobutyric acid transporter (VGAT) was necessary and sufficient for modeling these structural changes; VGAT levels gated the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation, and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation. HighlightsO_LIEnhancement of GABAergic transmission is a shared mechanism between LID and TD. C_LIO_LIVGAT levels in MSNs govern the structure and function of MSN presynaptic terminals. C_LIO_LIGain and loss of VGAT function in MSNs exacerbates and ameliorates dyskinesia. C_LIO_LILowered D2 signaling with repetitive DA fluctuations causes VGAT overexpression. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/550763v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@15041b4org.highwire.dtl.DTLVardef@9bf41org.highwire.dtl.DTLVardef@1eb7ee4org.highwire.dtl.DTLVardef@1d7dae8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗