Biology subjects

Lee, S.-H.

Publications and source records attributed to Lee, S.-H..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Ketamine reverses chronic stress-induced behavioral changes via the expression of Ca2+-permeable AMPA receptors in mice

Background and Purpose: Chronic stress affects brain functions leading to the development of mental disorders like anxiety and depression, as well as cognitive decline and social dysfunction. Among many biological changes in chronically stressed brains, disruptions in AMPA Receptor (AMPAR)-mediated synaptic transmission in the hippocampus are associated with stress responses. We have revealed that low-dose ketamine rapidly induces the expression of GluA1-containing, GluA2-lacking Ca2+-Permeable AMPARs (CP-AMPARs), which enhances glutamatergic synaptic strength in hippocampal neurons. Additionally, subanesthetic low-dose ketamine decreases anxiety- and depression-like behaviors in naive animals. In addition to reducing depression, some research indicates that ketamine may have protective effects against chronic stress in both humans and animals. However, the role of CP-AMPARs in the actions of ketamine's antistress effects is largely unknown. Experimental Approach: We use whole-cell patch-clamp recordings from CA1 pyramidal neurons in female and male hippocampal slices and multiple behavioral assays including reciprocal social interaction, contextual fear conditioning, and tail suspension test. Key Results: We demonstrate that low-dose ketamine treatment reverses chronic restraint stress (CRS)-induced social dysfunction, hippocampus-dependent fear memory loss, and depression-like behavior in both female and male mice. Furthermore, we show that the ketamine-induced antistress effects on these behaviors are dependent on CP-AMPARs. Conclusion and Implications: Our findings suggest that subanesthetic low-dose ketamine rapidly triggers synaptic insertion of CP-AMPARs in the hippocampus, which induces antidepressant and antistress effects.

neuroscience↗

bioRxiv2024

Systemic CD8+ T cell effector signature predicts prognosis of lung cancer immunotherapy

BackgroundWhile immune checkpoint inhibitors (ICIs) are adopted as standard therapy in non-small cell lung cancer (NSCLC) patients, factors that influence variable prognosis still remain elusive. Therefore, a deeper understanding is needed of how germline variants regulate the transcriptomes of circulating immune cells in metastasis, and ultimately influence immunotherapy outcomes. MethodsWe collected peripheral blood mononuclear cells (PBMCs) from 73 ICI-treated NSCLC patients, conducted single-cell RNA sequencing, and called germline variants via SNP microarray. Determination of expression quantitative trait loci (eQTL) allows elucidating genetic interactions between germline variants and gene expression. Utilizing aggregation-based eQTL mapping and network analysis across eight blood cell types, we sought cell-type-specific and ICI-prognosis-dependent gene regulatory signatures. ResultsOur sc-eQTL analysis identified 3,616 blood- and 702 lung-cancer-specific eGenes across eight major clusters and treatment conditions, highlighting involvement of immune-related pathways. Network analysis revealed TBX21-EOMES regulons activity in CD8+ T cells and the enrichment of eQTLs in higher-centrality genes as predictive factors of ICI response. ConclusionsOur findings suggest that in the circulating immune cells of NSCLC patients, transcriptomic regulation differs in a cell type- and treatment-specific manner. They further highlight the role of eQTL loci as broad controllers of ICI-prognosis-predicting gene networks. The predictive networks and identification of eQTL contributions can lead to deeper understanding and personalized ICI therapy response prediction based on germline variants.

genomics↗

bioRxiv2024

Precision Repair of Zone-Specific Meniscal Injuries Using a Tunable Extracellular Matrix-Based Hydrogel System

Meniscus injuries present significant therapeutic challenges due to their limited self-healing capacity and diverse biological and mechanical properties across meniscal tissue. Conventional repair strategies neglect to replicate the complex zonal characteristics within the meniscus, resulting in suboptimal outcomes. In this study, we introduce an innovative, age- and stiffness-tunable meniscus decellularized extracellular matrix (DEM)-based hydrogel system designed for precision repair of heterogeneous, zonal-dependent meniscus injuries. By synthesizing age-dependent DEM hydrogels, we identified distinct cellular responses: fetal bovine meniscus-derived DEM promoted chondrogenic differentiation, while adult meniscus-derived DEM supported fibrochondrogenic phenotypes. The incorporation of methacrylate hyaluronic acid (MeHA) further refined the mechanical properties and injectability of the DEM-based hydrogels. The combination of age-dependent DEM with MeHA allowed for precise stiffness tuning, influencing cell differentiation and closely mimicking native tissue environments. In vivo tests confirmed the biocompatibility of hydrogels and their integration with native meniscus tissues. Furthermore, advanced 3D bioprinting techniques enabled the fabrication of hybrid hydrogels with biomaterial and mechanical gradients, effectively emulating the zonal properties of meniscus tissue and enhancing cell integration. This study represents a significant advancement in meniscus tissue engineering, providing a promising platform for customized regenerative therapies across a range of heterogeneous fibrous connective tissues.

bioengineering↗

bioRxiv2024

Progressive overfilling of readily releasable pool underlies short-term facilitation at recurrent excitatory synapses in layer 2/3 of the rat prefrontal cortex

Short-term facilitation of recurrent excitatory synapses within the cortical network has been proposed to support persistent activity during working memory tasks, yet the underlying mechanisms remain poorly understood. We characterized short-term plasticity at the local excitatory synapses in layer 2/3 of the rat medial prefrontal cortex and studied its presynaptic mechanisms. Low-frequency stimulation induced slowly developing facilitation, whereas high-frequency stimulation initially induced strong depression followed by rapid facilitation. This non-monotonic delayed facilitation after a brief depression resulted from a high vesicular fusion probability and slow activation of Ca2+-dependent vesicle replenishment, which led to the overfilling of release sites beyond their basal occupancy. Pharmacological and gene knockdown (KD) experiments revealed that the facilitation was mediated by phospholipase C/diacylglycerol signaling and synaptotagmin 7 (Syt7). Notably, Syt7 KD abolished facilitation and slowed the refilling rate of vesicles with high fusion probability. Furthermore, Syt7 deficiency in layer 2/3 pyramidal neurons impaired the acquisition of trace fear memory and reduced c-Fos activity. In conclusion, Ca2+- and Syt7-dependent overfilling of release sites mediates synaptic facilitation at layer 2/3 recurrent excitatory synapses and contributes to temporal associative learning.

neuroscience↗

bioRxiv2024

Evidence for belief updating in decision-variable space: past decisions with finer granularity attract future ones more strongly

When engaged in decision-making tasks, humans are known to create decision variables. Much effort has focused on the cognitive processes involved in forming decision variables. However, there is limited understanding of how decision variables, once formed, are utilized to adapt to the environment. We reason that decision-makers would benefit from updating the belief of decision-variable. As one such belief updating, we hypothesize that a decision commitment restricts the probabilistic belief distribution of decision variable to a range corresponding to that decision. This implies that past decisions not only attract future ones but also exert a greater pull when those decisions are made with finer granularity-- dubbed the granularity effect. Here, we present the findings of seven psychophysical experiments that confirm these implications. Further, as a unified account of the granularity effect, we offer a Bayesian model. Our work demonstrates how humans leverage the decision-variable to effectively adapt to their surroundings.

neuroscience↗

bioRxiv2024

Prelimbic corticopontine neurons gate extinction learning

The prelimbic cortex is essential for association of temporally separated events, and impedes extinction of learned association. The network mechanism underlying reversal learning, however, remains elusive. Here, we found that mitochondria-dependent post-tetanic potentiation at synapses onto prelimbic corticopontine neurons impedes extinction learning without affecting initial associative learning. Rats underwent trace fear conditioning followed by extinction sessions. Pharmacological inhibition of post-tetanic potentiation using tetaraphenylphosphnium (TPP), a mitochondrial Ca2+ release blocker, accelerated extinction of trace fear memory, leaving trace fear memory formation intact. Optogenetic inhibition of corticopontine, but not commissural, neurons phenocopied these effects. Electrophysiological recordings and Ca2+ imaging revealed that TPP treatment reduced the persistent activity of corticopontine neurons encoding tone presentation. Mechanistically, associative learning triggers the bursting activity of prelimbic pyramidal neurons that induces post-tetanic potentiation of corticopontine neurons, an effect blocked by TPP treatment. Thus, we identified a prelimbic cell type- and local circuit-specific mechanism that selectively gates extinction learning.

neuroscience↗

bioRxiv2024

3D printed microtissue cassettes enabling high throughput proton radiobiological assays

Uncertainties on proton relative biological effectiveness (RBE) across the spread out of Bragg peak (SOBP) (typically assumed to be 1.1) may lead to suboptimal treatment plan and unwarranted toxicity to organs-at-risk. Herein, we report a reliable analytical method to determine the proton RBE along the SOBP and distal fall-off region. The 3D microtissue cassette enables the high throughput assessment of biological assays including clonogenic assay and {gamma}-H2AX assay following a single proton irradiation. Clonogenic assay shows the RBE of 1.6 (10% cellular survival) which is consistent with the deter-mined RBE of 1.58 using the {gamma}-H2AX assay. Besides, we also show that the high spatial resolution of the cassette can distinguish the minute but significant foci changes (number, area) in response to small proton radiation dose fraction. The results validate the reliability of our setup in addressing critical proton radiobiological questions.

bioengineering↗

bioRxiv2024

The multi-level effect of chlorpyrifos during clownfish metamorphosis

Chemical pollution in coastal waters, particularly from agricultural runoff organophosphates, poses a significant threat to marine ecosystems, including coral reefs. Pollutants such as chlorpyrifos (CPF) are widely used in agriculture and have adverse effects on marine life and humans. In this paper, we investigate the impact of CPF on the metamorphosis of a coral reef fish model, the clownfish Amphiprion ocellaris, focusing on the disruption of thyroid hormone (TH) signalling pathways. Our findings reveal that by reducing TH levels, CPF exposure impairs the formation of characteristic white bands in clownfish larvae, indicative of metamorphosis progression. Interestingly, TH treatment can rescue these effects, establishing a direct causal link between CPF effect and TH disruption. The body shape changes occurring during metamorphosis are also impacted by CPF exposure, shape changes are less advanced in CPF-treated larvae than in control conditions. Moreover, transcriptomic analysis elucidates CPFs effects on all components of the TH signalling pathway. Additionally, CPF induces systemic effects on cholesterol and vitamin D metabolism, DNA repair, and immunity, highlighting its broader TH-independent impacts. Pollutants are often overlooked in marine ecosystems, particularly in coral reefs. Developing and enhancing coral reef fish models, such as Amphiprion ocellaris, offers a more comprehensive understanding of how chemical pollution affects these ecosystems. This approach provides new insights into the complex mechanisms underlying CPF toxicity during fish metamorphosis, shedding light on the broader impact of environmental pollutants on marine organisms. HighlightsO_LIChlorpyrifos (CPF) is an insecticide widely used in agriculture for the past five decades and has adverse effects on marine life and humans C_LIO_LICPF exposure impairs the formation of characteristic white bands in clownfish larvae, indicative of metamorphosis progression C_LIO_LIDuring metamorphosis, clownfish larvae lose their elongated body shape and transform into miniature ovoid-shaped adults, these shape changes are less advanced in CPF-treated larvae C_LIO_LICPF induces systemic effects on cholesterol and vitamin D metabolism, DNA repair, and immunity, highlighting its broader TH-independent impacts C_LI

developmental biology↗

bioRxiv2024

Time-resolved tracking of cellulose biosynthesis and microfibril network assembly during cell wall regeneration in live Arabidopsis protoplasts

Significance StatementCellulose is a major extracellular matrix component of cells that is critical for plant development and has applications to bioenergy, agricultural food/feed, textile, and wood production. Cellulose is thought to be assembled by the closely coordinated motion of plasma membrane-embedded cellulose synthase enzyme complexes. To date, however, it has not been possible to visualize de novo plant cell wall synthesis at the single cell level with the necessary spatiotemporal resolution to derive a data-driven model of how plant cells can resynthesize and assemble cell wall after its removal. Based on our time-resolved data, we propose a new model for cellulose biosynthesis after successfully performing live protoplast time-lapse imaging to visualize for the first time the complex dynamics of de novo cellulose biosynthesis and assembly into an intertwined microfibril network. Plant cell walls are composed of polysaccharides among which cellulose is the most abundant component. Cellulose is processively synthesized as bundles of linear {beta}-1,4-glucan homopolymer chains via the coordinated action of multiple enzymes in cellulose synthase complexes (CSCs) embedded within the plasma cell membrane. Plant cell walls are composed of multiple layers of cellulose fibrils that form highly intertwined extracellular matrix networks. However, it is not yet clear as to how cellulose fibrils synthesized by multiple CSCs are assembled into the intricate cellulose network deposited on plant cell surfaces. Herein, we have established an in vivo time-resolved imaging platform for visualizing cellulose during its biosynthesis and assembly into a complex fibrillar network on the surface of Arabidopsis thaliana mesophyll protoplasts as the primary cell wall regenerates. We performed total internal reflection fluorescence microscopy (TIRFM) with fluorophore-conjugated tandem carbohydrate binding modules (tdCBMs) that were engineered to specifically bind to nascent cellulose fibrils. Together with a well-controlled environment, it was possible to monitor in vivo cellulose fibril synthesis dynamics in a time-resolved manner for nearly one day of continuous cell wall regeneration on protoplast cell surfaces. Our observations provide the basis for a novel model of cellulose fibril network development in protoplasts driven by complex interplay of multi-scale dynamics that include: rapid diffusion and coalescence of short nascently synthesized cellulose fibrils; processive elongation of single fibrils; and cellulose fibrillar network rearrangement during cell wall maturation. This platform is valuable for exploring mechanistic aspects of cell wall synthesis while visualizing cellulose microfibrils assembly.

plant biology↗

bioRxiv2024

Epigenetic Dynamics in Meniscus Cell Migration and its Zonal Dependency in Response to Inflammatory Conditions: Implications for Regeneration Strategies

Meniscus injuries pose significant challenges in clinical settings, primarily due to the intrinsic heterogeneity of the tissue and the limited efficacy of current treatments. Endogenous cell migration is crucial for the healing process, yet the regulatory mechanisms of meniscus cell migration and its zonal dependency within the meniscus are not fully understood. Thus, this study investigates the role of epigenetic mechanisms in governing meniscus cell migration under inflammatory conditions, with a focus on their implications for injury healing and regeneration. Here, we discovered that a proinflammatory cytokine, TNF- treatment significantly impedes the migration speed of inner meniscus cells, while outer meniscus cells are unaffected, underscoring a zonal-dependent response within the meniscus. Our analysis identified distinct histone modification patterns and chromatin dynamics between inner and outer meniscus cells during migration, highlighting the necessity to consider these zonal-dependent properties in devising repair strategies. Specifically, we found that TNF- differentially influences histone modifications, particularly H3K27me3, between the two cell types. Transcriptome analysis further revealed that TNF- treatment induces substantial gene expression changes, with inner meniscus cells exhibiting more pronounced alterations than outer cells. Gene cluster analysis pointed to distinct responses in chromatin remodeling, extracellular matrix assembly, and wound healing processes between the zonal cell populations. Moreover, we identified potential therapeutic targets by employing existing epigenetic drugs, GSKJ4 (a histone demethylase inhibitor) and C646 (a histone acetyltransferase inhibitor), to successfully restore the migration speed of inner meniscus cells under inflammatory conditions. This highlights their potential utility in treating meniscus tear injuries. Overall, our findings elucidate the intricate interplay between epigenetic mechanisms and meniscus cell migration, along with its meniscus zonal dependency. This study provides insights into potential targets for enhancing meniscus repair and regeneration, which may lead to improved clinical outcomes for patients with meniscus injuries and osteoarthritis.

bioengineering↗

bioRxiv2024

STK19 drives Transcription-Coupled Repair by stimulating repair complex stability, Pol II ubiquitylation and TFIIH recruitment

DNA damage forms a major obstacle for gene transcription by RNA polymerase II (Pol II). Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates transcription-blocking lesions (TBLs), thereby safeguarding accurate transcription, preserving correct cellular function and counteracting aging. TC-NER initiation involves the recognition of lesion-stalled Pol II by CSB, which recruits the CRL4CSA E3 ubiquitin ligase complex and UVSSA. TBL-induced ubiquitylation of Pol II at lysine 1268 of the RPB1 subunit by CRL4CSA serves as a critical TC-NER checkpoint, governing Pol II stability and initiating TBL excision by TFIIH recruitment. However, the precise regulatory mechanisms of the CRL4CSA E3 ligase activity and TFIIH recruitment remain elusive. Here, we reveal Inactive Serine/Threonine Kinase 19 (STK19) as a novel TC-NER factor, that is essential for correct TBL removal repair and subsequent transcription restart. Cryo-EM studies demonstrate that STK19 is an integral part of the Pol II-TC-NER complex, bridging CSA with UVSSA, RPB1 and downstream DNA. Live-cell imaging and interaction studies show that STK19 stimulates TC-NER complex stability and CRL4CSA activity, resulting in efficient Pol II ubiquitylation and correct UVSSA and TFIIH binding. These findings underscore the crucial role of STK19 as a core component of the TC-NER machinery and its key involvement in the cellular responses to DNA damage that interfere with transcription.

molecular biology↗

bioRxiv2024

Cellular dsRNA interactome reveals the regulatory map of exogenous RNA sensing

RNA-binding proteins (RBPs) provide a critical post-transcriptional regulatory layer in determining RNA fate. Currently, UV crosslinking followed by oligo-dT pull-down is the golden standard in identifying the RBP repertoire, but such method is ineffective in capturing RBPs that recognize double-stranded RNAs (dsRNAs). Here, we utilize anti-dsRNA antibody immunoprecipitation followed by quantitative mass spectrometry to comprehensively identify RBPs bound to cellular dsRNAs without any external stimulus. Notably, our dsRNA interactome contains proteins involved in sensing N6-methyladenosine RNAs and stress granule components. We further perform targeted CRISPR-Cas9 knockout functional screening and discover proteins that can regulate the interferon (IFN) response during exogenous RNA sensing. Interestingly, depleting dsRBPs mostly attenuate the IFN response, and they act as antiviral factors during human {beta}-coronavirus HCoV-OC43 infection. Our dsRNA interactome capture provides an unbiased and comprehensive characterization of putative dsRBPs and will facilitate our understanding of dsRNA sensing in both physiological and pathological contexts.

molecular biology↗

bioRxiv2024

Determination of the absolute concentration of Rayleigh particles via scattering microscopy

Nanoparticles are crucial in diverse fields such as healthcare, electronics, and energy. Their small size allows them to cross biological barriers, enhancing drug delivery but also posing health risks. Accurate characterization of nanoparticles is essential for assessing their safety and efficacy, particularly in medical applications. Traditional methods such as dynamic light scattering and mass spectrometry have limitations in sensitivity and range of application. To address these challenges, we introduce the interferometric Concentration Analyzer and Ultrasmall Nanoparticle Tracker (iCAUNT), a technique for detecting and quantifying nanoparticles smaller than one-tenth of the imaging light wavelength. As a non-invasive method, iCAUNT provides precise size and concentration measurements of biological and synthetic nanoparticles, offering significant potential for diagnostics, therapeutics, and broader nanoscience applications.

biophysics↗

bioRxiv2024

Structural and Biophysical Dynamics of Fungal Plasma Membrane Proteins and Implications for Echinocandin Action in Candida glabrata

Fungal plasma membrane proteins represent key therapeutic targets for antifungal agents, yet their structure and spatial distribution in the native context remain poorly characterized. Herein, we employ an integrative multimodal approach to elucidate the structural and functional organization of plasma membrane protein complexes in Candida glabrata, focusing on prominent and essential membrane proteins, the polysaccharide synthase {beta}-(1,3)-glucan synthase (GS) and the proton pump Pma1. Cryo-electron tomography (cryo-ET) and live cell imaging reveal that GS and Pma1 are heterogeneously distributed into distinct plasma membrane microdomains. Treatment with caspofungin, an echinocandin antifungal that targets GS, alters the plasma membrane and disrupts the native distribution of GS and Pma1. Based on these findings, we propose a model for echinocandin action that considers how drug interactions with the plasma membrane environment lead to inhibition of GS. Our work underscores the importance of interrogating the structural and dynamic characteristics of fungal plasma membrane proteins in situ to understand function and facilitate precisely targeted development of novel antifungal therapies.

cell biology↗

bioRxiv2024

Hypothalamus-specific NSCs derived from hPSCs ameliorate age-associated dysfunction upon transplantation into aged mouse hypothalamus

The hypothalamus is the brain region that regulates systemic body metabolism and multiple brain functions. The adult hypothalamus harbors neural stem/precursor cell (NSC)-like cells. Along with age-related body changes, the hypothalamic NSC (htNSC) population declines, indicating the potential of htNSC replacement as an anti-aging strategy. Here, we developed protocol to generate htNSCs from human pluripotent stem cells (hPSCs). Implanting the hPSC-derived htNSCs into the hypothalamus of aged mice ameliorated age-related declines in metabolic fitness, physical capacity, and cognitive function. Mechanistically, these anti-aging effects were mediated by inter-tissue communication: enhanced neuronal activity in the htNSC-transplanted hypothalamus stimulated adipose tissues to produce and release the anti-aging molecule eNAMPT into systemic circulation via the sympathetic nervous system. Concurrently, the aged inflammatory environment in the hypothalamus was alleviated by peripheral anti-aging signals. Collectively, our findings support the potential of anti- or healthy aging therapies by targeting hypothalamus.

cell biology↗

bioRxiv2024

Unveiling the influence of tumor and immune signatures on immune checkpoint therapy in advanced lung cancer

This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICI). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (AUC) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.

bioinformatics↗

bioRxiv2024

Activation of hypoactive parvalbumin-positive fast-spiking interneuron restores dentate inhibition to prevent epileptiform activity in the mouse intrahippocampal kainate model of temporal lobe epilepsy

Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ interneuron mediated inhibition is compromised in the dentate gyrus shortly after status epilepticus, contributing to epileptogenesis in temporal lobe epilepsy. It is uncertain whether the impaired activity of dentate PV+ interneurons recovers at later times or if it continues for months following status epilepticus. The development of compensatory modifications related to PV+ interneuron circuits in the months following status epilepticus is unknown, although reduced dentate GABAergic inhibition persists long after status epilepticus. We employed PV immunostaining and whole-cell patch-clamp recordings from dentate PV+ interneurons and DGCs in slices from male and female sham controls and intrahippocampal kainate (IHK) treated mice that developed spontaneous seizures months after status epilepticus to study epilepsy-associated changes in dentate PV+ interneuron circuits. We found that the number of dentate PV+ cells was reduced in IHK treated mice. Electrical recordings showed that: 1) Action potential firing rates of dentate PV+ interneurons were reduced in IHK treated mice up to four months after status epilepticus; 2) Spontaneous inhibitory postsynaptic currents (sIPSCs) in DGCs exhibited reduced frequency but increased amplitude in IHK treated mice; and 3) The amplitude of evoked IPSCs in DGCs by optogenetic activation of dentate PV+ cells was upregulated without changes in short-term plasticity. Video-EEG recordings revealed that IHK treated mice showed spontaneous epileptiform activity in the dentate gyrus and that chemogenetic activation of PV+ interneurons abolished the epileptiform activity. Our results suggest not only that the compensatory changes in PV+ interneuron circuits develop after IHK treatment, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for cell loss and reduced intrinsic excitability of dentate PV+ interneurons to stop seizures in temporal lobe epilepsy. HighlightsO_LIReduced number of dentate PV+ interneurons in TLE mice C_LIO_LIPersistently reduced action potential firing rates of dentate PV+ interneurons in TLE mice C_LIO_LIEnhanced amplitude but decreased frequency of spontaneous IPSCs in the dentate gyrus in TLE mice C_LIO_LIIncreased amplitude of evoked IPSCs mediated by dentate PV+ interneurons in TLE mice C_LIO_LIChemogenetic activation of PV+ interneurons prevents epileptiform activity in TLE mice C_LI

neuroscience↗

bioRxiv2024

Neuroprotective role of Hippo signaling by microtubule stability control in C. elegans

The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in C. elegans. Loss of wts-1/LATS, the core kinase of the Hpo pathway, resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/YAP-dependent manner, the downstream transcriptional co-activator of LATS. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.

developmental biology↗