Biology subjects

Xiao, Y.

Publications and source records attributed to Xiao, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2024

Spatiotemporal Single-Cell Roadmap of Human Skin Wound Healing

Wound healing is vital for human health, yet the details of cellular dynamics and coordination in human wound repair remain largely unexplored. To address this, we conducted single-cell and spatial transcriptomics analyses on human skin and acute wound tissues through inflammation, proliferation, and remodeling phases of wound repair from the same individuals, monitoring the cellular and molecular dynamics of human skin wound healing at an unprecedented spatiotemporal resolution. This singular roadmap reveals the cellular architecture of the wound margin and identifies FOSL1 as a critical driver of re-epithelialization. It shows that pro-inflammatory macrophages and fibroblasts sequentially support keratinocyte migration like a relay race across different healing stages. Comparison with single-cell data from venous and diabetic foot ulcers uncovers a link between failed keratinocyte migration and impaired inflammatory response in chronic wounds. Additionally, comparing human and mouse acute wound transcriptomes underscores the indispensable value of this roadmap in bridging basic research with clinical innovations. HighlightsO_LIA spatiotemporal atlas to explore human in vivo gene expression across wound healing C_LIO_LIWound margin architecture unveils a model for human re-epithelialization C_LIO_LIDistinct healing challenges in venous ulcers and diabetic foot ulcers C_LIO_LIUnique human healing traits emerge in cellular heterogeneity and gene expression C_LI

cell biology↗

bioRxiv2024

Proteolysis targeting chimera extracellular vesicles for therapeutic development treating triple negative breast cancer

Proteolysis targeting chimeras (PROTACs) are an emerging targeted cancer therapy approach, but wide-spread clinical use of PROTAC is limited due to poor cell targeting and penetration, and instability in vivo. To overcome such issues and enhance the in vivo efficacy of PROTAC drugs, microfluidic droplet-based electroporation ({micro}DES) was developed as a novel extracellular vesicle (EVs) transfection system, which enables the high-efficient PROTAC loading and effective delivery in vivo. Our previously developed YX968 PROTAC drug had shown the selectively degradation of HDAC3 and 8, which effectively suppresses the growth of breast tumor cell lines, including MDA-MB-231 triple negative breast cancer (TNBC) line, via dual degradation without provoking a global histone hyperacetylation. In this study, we demonstrated that {micro}DES-based PROTAC loading in EVs significantly enhanced therapeutic function of PROTAC drug in vivo in the TNBC breast tumor mouse model. NSG mice with pre-established MDA-MB-231 tumors and treated with intraperitoneal injection of EVs for tumor inhibition study, which showed significantly higher HDAC 3 and 8 degradation efficiency and tumor inhibition than PROTAC only group. The liver, spleen, kidney, lung, heart, and brain were collected for safety testing, which exhibited improved toxicity. The EV delivery of PROTAC drug enhances drug stability and bioavailability in vivo, transportability, and drug targeting ability, which fills an important gap in current development of PROTAC therapeutic functionality in vivo and clinical translation. This novel EV-based drug transfection and delivery strategy could be applicable to various therapeutics for enhancing in vivo delivery, efficacy, and safety.

bioengineering↗

bioRxiv2024

Modelling medulloblastoma pathogenesis and treatment in human cerebellar organoids.

Faithful genetically engineered in vivo models of medulloblastoma (MB) are currently available only for some molecular subgroups, in keeping with recent studies showing the unique role of human-specific progenitors in the development of G3 and G4 MB subgroups. We generated human cerebellar organoids (CbO) from expanded potential stem cells (EPSC) and characterised their epigenetic and transcriptomic profile compared to the developing human cerebellum. We show the presence of sub compartment-specific cerebellar lineages linked to MB formation, including populations expressing signature genes of putative G3 and G4 MB cells-of-origin. We show that these lineages can be genetically engineered to model MB tumour onset. Moreover, we demonstrate that CbO sustain proliferation and invasion of G3/4 MB cells in a 3D co-culture model (CbO-MB) while preserving their molecular identity, and that treatment of CbO-MB with anti-tumour compounds recapitulate the efficacy of in vivo drug testing in xenograft models.

cancer biology↗

bioRxiv2024

Models of microbiome evolution incorporating host resource provisioning

Multicellular hosts and their associated microbial partners (i.e., microbiomes) often interact in mutually beneficial ways. Consequently, hosts may choose to allocate resources to regulate and recruit appropriate microbes. In doing so, hosts may incur an energetic cost, and in turn, these costs can affect host fitness. It remains unclear how hosts have evolved to balance the costs of expending resources to manage their microbiomes against the benefits that might accrue by doing so. We extended a previously-developed agent-based computational model of hostmicrobiome evolution by incorporating a resource provisioning process, whereby hosts provide resources to support beneficial microbes and suppress harmful microbes, with attendant fitness costs. Our results indicate that the ways and sources from which a host acquires microbes are crucial factors influencing the hosts willingness to provide resources, to regulate microbiome composition. The intensity of resource provisioning will depend, in part, on how much of their microbiome hosts contribute to, and obtain from, their environment: when hosts that engage in resource provisioning contribute a high percentage of their microbiome to the environment, then there is less evolutionary imperative for other hosts to also provide resources. Since resource provisioning incurs a fitness cost to the host, over evolutionary time, resource provisioning will not be favored. Additionally, if selection at the microbial level is not sufficiently strong, and the host obtains a high proportion of microbes from the environment, then the higher the proportion of beneficial microbes in the environment, the less the host is willing to provide resources.

microbiology↗

bioRxiv2024

The molecular basis of Human FN3K mediated phosphorylation of glycated substrate

Glycation, a non-enzymatic post-translational modification occurring on proteins, can be actively reversed via site-specific phosphorylation of the fructose-lysine moiety by FN3K kinase, to impact the cellular function of target protein. A regulatory axis between FN3K and glycated protein targets has been associated with conditions like diabetes and cancer. However the molecular basis of this relationship has not been explored so far. Here, we determined a series of crystal structures of HsFN3K in apo-state, and in complex with different nucleotide analogs together with a sugar substrate mimic to reveal the features important for its kinase activity and substrate recognition. Additionally, the dynamics in sugar substrate binding during the kinase catalytic cycle provide important mechanistic insights into HsFN3K function. Our structural work provides the molecular basis for rationale small molecule design targeting FN3K.

biochemistry↗

bioRxiv2024

CRISPR-mediated chromosome deletion facilitates genetic mapping of Vip3Aa resistance gene within complex genomic region in an invasive global pest

Connecting genetic variation to phenotypes and understanding the underlying biological mechanisms has been a fundamental goal of biological genetics. Here, we used the association analysis to identify a Vip3Aa resistance-associated genomic region in a strain of fall armyworm, JC-R, which exhibits >5000-fold resistance to the Bt toxin Vip3Aa. However, through various analytical approaches and fine-scale mapping across different populations, we demonstrated that this genomic region exhibits strong genetic linkage. The chromosome-level genome of JC-R and its parent strain JC-S were assembled, and extensive structural variations in the linkage regions were identified, which could be responsible for maintaining the linkage. To identify the causal variation within this linked region, a chromosome fragment stepwise knockout strategy based on CRISPR/Cas9 was developed. By crossing with the resistant strain and phenotyping segregating offspring on Vip3Aa-containing diet, we identified a chromosomal segment, KO8, containing the resistant gene. Subsequently, we conducted a comprehensive analysis of the variations in the KO8 region using multi-omics approaches, including genomic data, RNA-seq, proteomic, PacBio long read Iso-seq, and phosphoproteomic data. This analysis identified multiple variations in the chitin synthase gene CHS2, including amino acid substitution, alternative splicing, and changes in phosphorylation sites. After knocking out the CHS2, larvae exhibited over 6777-fold resistance to Vip3Aa. These results demonstrate that the chromosome fragment stepwise knockout strategy is a viable approach for studying complex genomic regions, and highlight the value of comprehensive analysis of genetic variations using multi-omics data. The identified candidate gene could potentially advance monitoring and management of pest resistance to Vip3Aa.

genetics↗

bioRxiv2024

Coordinated regulation of chemotaxis and resistance to copper by CsoR in Pseudomonas putida

Copper is an essential enzyme cofactor in bacteria, but excess copper is highly toxic. Bacteria can cope with copper stress by increasing copper resistance and initiating chemorepellent response. However, it remains unclear how bacteria coordinate chemotaxis and resistance to copper. By screening proteins that interacted with the chemotaxis kinase CheA, we identified a copper-binding repressor CsoR that interacted with CheA in Pseudomonas putida. CsoR interacted with the HPT (P1), Dimer (P3), and HATPase_c (P4) domains of CheA and inhibited CheA autophosphorylation, resulting in decreased chemotaxis. The copper-binding of CsoR weakened its interaction with CheA, which relieved the inhibition of chemotaxis by CsoR. In addition, CsoR bound to the promoter of copper-resistance genes to inhibit gene expression, and copper-binding released CsoR from the promoter, leading to increased gene expression and copper resistance. P. putida cells exhibited a chemorepellent response to copper in a CheA-dependent manner, and CsoR inhibited the chemorepellent response to copper. Besides, the CheA-CsoR interaction also existed in proteins from several other bacterial species. Our results revealed a mechanism by which bacteria coordinately regulated chemotaxis and resistance to copper by CsoR.

microbiology↗

bioRxiv2024

Role of Kir4.1/Kir5.1 in mediating Angiotensin-II (Ang-II)-induced stimulation of thiazide-sensitive Na-Cl cotransporter.

BackgroundAngiotensin-II (Ang-II) perfusion stimulates Kir4.1/Kir5.1 in the distal-convoluted-tubule (DCT) and thiazide-sensitive Na-Cl-cotransporter (NCC). However, the role of Kir4.1/Kir5.1 in mediating the effect of Ang-II on NCC is not understood. MethodsWe used immunoblotting and patch-clamp-experiments to examine whether Ang-II-induced stimulation of NCC is achieved by activation of Kir4.1/Kir5.1 of the DCT using kidney-renal-tubule-specific AT1aR-knockout (Ks-AT1aR-KO), Ks-Kir4.1-knockout and the corresponding wild-type mice. ResultsAng-II perfusion for 1, 3 and 7 days progressively increased phosphor-NCC (pNCC) and total-NCC (tNCC) expression and the effect of Ang-II-perfusion on pNCC and tNCC was abolished in Ks-AT1aR-KO. Ang-II perfusion for 1-day robustly stimulates Kir4.1/Kir5.1 in the late DCT (DCT2) and to a lesser degree in the early DCT (DCT1), an effect was absent in Ks-AT1aR-KO mice. However, Ang-II perfusion for 7-days did not further stimulate Kir4.1/Kir5.1 in the DCT2 and only modestly increased Kir4.1/Kir5.1-mediated K+ currents in DCT1. Deletion of Kir4.1 not only significantly decreased the expression of pNCC and tNCC but also abolished the effect of 1-day Ang-II perfusion on the expression of phospho-with-no-lysine-kinase-4 (pWNK4), phosphor-ste-20-proline-alanine-rich-kinase (pSPAK), pNCC and tNCC. However, 7-days Ang-II perfusion was still able to significantly stimulate the expression of pSPAK, pWNK4, pNCC and tNCC, and increased thiazide-induced natriuresis in kidney-tubule-specific Kir4.1 knockout (Ks-Kir4.1 KO) mice without obvious changes in K+ channel activity in the DCT. ConclusionsShort-term Ang-II induced stimulation of pWNK4, pSPAK and pNCC depends on Kir4.1/Kir5.1 activity. However, long-term Ang-II is able to directly stimulate pWNK4, pSPAK and pNCC by a Kir4.1/Kir5.1 independent mechanism.

physiology↗

bioRxiv2024

SPACEc: A Streamlined, Interactive Python Workflow for Multiplexed Image Processing and Analysis

Multiplexed imaging technologies provide insights into complex tissue architectures. However, challenges arise due to software fragmentation with cumbersome data handoffs, inefficiencies in processing large images (8 to 40 gigabytes per image), and limited spatial analysis capabilities. To efficiently analyze multiplexed imaging data, we developed SPACEc, a scalable end-to-end Python solution, that handles image extraction, cell segmentation, and data preprocessing and incorporates machine-learning-enabled, multi-scaled, spatial analysis, operated through a user-friendly and interactive interface.

bioinformatics↗

bioRxiv2024

Tracing neurodiverse disruptions underlying emotional episodic memory to diagnosis-specific network of emotional regulation in psychiatric disorders

BackgroundAffective symptoms are a prevalent psychopathological feature in various psychiatric disorders. However, the underlying neurobiological mechanisms are complex and not yet fully understood. MethodsWe used normative modelling to establish a reference for neurofunctional activation of functional magnetic resonance imaging based on an emotional episodic memory task, which is frequently used to study affective symptoms in psychiatric disorders. This normative reference was derived from a large dataset of healthy individuals (n = 409), and used to evaluate individualized functional alterations by calculating deviations from this reference in a clinical dataset of 328 participants, which included 168 healthy controls and patients with major depressive disorder (MDD, n = 56), bipolar disorder (BD, n = 31), and schizophrenia (SZ, n = 73). The neurofunctional deviations were mapped to emotional networks with specific emotional functions and used to predict affective symptoms in different mental disorders. The microscale cellular signatures underlying macroscale variations were identified using imaging transcriptomic analysis, and associated with affective symptoms. ResultsWe observed distinct patterns of cross-scale neural alterations linked to affective symptoms in three psychiatric disorders. Macroscale neural dysfunctions in distinct disorders were embedded into non-overlapping emotional networks and significantly associated with affective symptoms. The oligodendrocytes may mediate the network-specific impairments, and microglia for MDD, astrocytes for BD, and excitatory neurons for SZ as replicable cell-type correlates of affective symptoms. ConclusionsThese findings have potential implications for the understanding of unique neuropathological patterns of affective symptoms in distinct psychiatric disorders and improving individualized treatment response.

neuroscience↗

bioRxiv2024

Eco-evolutionary Guided Pathomic Analysis to Predict DCIS Upstaging

Cancers evolve in a dynamic ecosystem. Thus, characterizing cancers ecological dynamics is crucial to understanding cancer evolution and can lead to discovering novel biomarkers to predict disease progression. Ductal carcinoma in situ (DCIS) is an early-stage breast cancer characterized by abnormal epithelial cell growth confined within the milk ducts. In this study, we show that ecological analysis of hypoxia and acidosis biomarkers can significantly improve prediction of DCIS upstaging. First, we developed a novel eco-evolutionary designed approach to define habitats in the tumor intraductal microenvironment based on oxygen diffusion distance. Then, we identified cancer cells with metabolic phenotypes attributed to their habitats, including CA9 for hypoxia responding phenotype, and LAMP2b for acid adapted phenotype. Traditionally these markers have shown limited predictive capabilities for DCIS progression, if any. However, when analyzed from an ecological perspective, their power to differentiate between non-upstaged and upstaged DCIS increased significantly. Second, we discovered distinct niches with spatial patterns of these biomarkers and used the distribution of such niches to predict patient upstaging. The niches were characterized by pattern analysis of both cellular and spatial features. With a 5-fold validation on the biopsy cohort, we trained a random forest classifier to achieve the area under curve (AUC) of 0.74. Our results affirm the importance of tumor ecological features in eco-evolutionary-designed approaches for novel biomarkers discovery. SignificanceOur results affirm the importance of spatial and ecological features in eco-evolutionary-designed biomarkers discovery studies in the era of digital pathology.

cancer biology↗

bioRxiv2024

Tailoring the self-blinking of sulfonamide rhodamine for long-term protein-localizing super-resolution imaging

Life continually changes its protein arrangements, yet the molecular ultradetails are covered by the short-lived deficiency of fluorophore blinking for super-resolution imaging. Herein, we proposed a crowding strategy to conserve the self-blinking events for prolonging the imaging time. We engineered sulfonamide rhodamines through atom-radii expansion (O-C-Si), rationally reversing xanthene intersection and creating stacking to enhance ring-opening energetical barriers. Our stacked rhodamines demonstrated decreased recruiting rates and extended survival lifetimes at single-molecule level, validating the decreased self-blinking kinetics from stacking strategy. Accordingly, our silicon-substituted rhodamine enabled persistent molecular localization imaging of various sub-organelle proteins to state-of-art time (0.5 h) in living cells, with versatile capabilities for three-dimensional and dual-color imaging. We envision our crowding strategy sets a new stage for prolongating super-resolution imaging through structural engineering.

biochemistry↗

bioRxiv2024

Multiple bouts of blood feeding in mosquitoes allow prolonged survival and are predicted to increase viral transmission during drought

Survival through periods of drought is critical for mosquitoes to reside in semi-arid regions with humans. Dry conditions increase blood feeding propensity in mosquitoes, but it is unknown if dehydration-induced bloodmeals increase feeding beyond what is necessary for reproduction. Following a bloodmeal, prolonged exposure to dry conditions increased secondary blood feeding in mosquitoes by nearly two-fold, and chronic blood feeding allowed mosquitoes to survive up to twenty days without access to water sources. This refeeding did not alter the number of eggs generated, suggesting this refeeding is for hydration and nutrient replenishment. Exposure to desiccating conditions following a bloodmeal resulted in increased activity, decreased sleep levels, and prompted a return of CO2 sensing before egg deposition. Increased blood feeding during the vitellogenic stage and higher survival during dry periods are predicted to increase pathogen transmission, allowing for a rapid rebound in mosquito populations when more favorable conditions return. This explains the elevated levels of specific arbovirus cases in association with periodic dry conditions and warrants further consideration as climate change progresses. Overall, these results solidify our understanding of the role of dry periods on mosquito blood feeding and how mosquito dehydration contributes to vectorial capacity and disease transmission dynamics Significance statementBouts of dehydration yield substantial changes to insects physiology and behavior. Mosquitoes are exceptionally prone to dehydration due to high water loss rates, but few integrative studies have examined the comprehensive impact of drought conditions on mosquitoes. Here, we demonstrate that dry conditions lead to multiple blood feeding events, allowing mosquitoes to survive dry periods. This repeated blood feeding is associated with higher activity and an early return of attraction to vertebrate hosts. Increased dry season survival and more frequent blood feeding are predicted to yield higher transmission of mosquito-borne viruses. This suggests that a higher prevalence of drought associated with climate change will have varying impacts on mosquito-borne diseases.

physiology↗

bioRxiv2024

KIPK and KIPK-LIKE1 suppress overbending during negative hypocotyl gravitropic growth

Plants use environmental cues, such as the direction of gravity or the direction, quantity and quality of light, to orientate organ and plant growth. During germination of angiosperm seeds in the soil, hypocotyl elongation is directed by negative gravitropism responses such that the seedling can reach the light for photosynthesis and autotrophic growth. Hypocotyl elongation in the soil, however, also requires mechanisms to efficiently grow around obstacles such as soil particles. Here, we identify KIPK (KINESIN-LIKE CALMODULIN-BINDING PROTEIN INTERACTING PROTEIN KINASE) and the paralogous KIPKL1 (KIPK-LIKE1) as genetically redundant regulators of hypocotyl bending, in that KIPK and KIPKL1 are required to efficiently align hypocotyl growth with the gravity vector after obstacle avoidance. At the same time, we find that the highly homologous KIPKL2 (KIPK-LIKE2) must be functionally distinct. We further find that KIPK, and likely also KIPKL1, phosphorylate BRXL2 (BREVIS RADIX LIKE2) and ARKs (ARMADILLO REPEAT KINESINs), that mutants of both KIPK phosphorylation substrates share the overbending phenotype with kipk kipkl1 mutants, and that KIPK and KIPKL1 act synergistically with the ARK-regulatory NEK6 (NIMA-RELATED PROTEIN KINASE6). We propose that KIPK and KIPKL1 regulate ARK kinesins and thereby cortical microtubules for efficient gravitropic hypocotyl bending.

plant biology↗

bioRxiv2024

Temperature-Dependent Fold-Switching Mechanism of the Circadian Clock Protein KaiB

The oscillator of the cyanobacterial circadian clock relies on the ability of the KaiB protein to switch reversibly between a stable ground-state fold (gsKaiB) and an unstable fold-switched fold (fsKaiB). Rare fold-switching events by KaiB provide a critical delay in the negative feedback loop of this post-translational oscillator. In this study, we experimentally and computationally investigate the temperature dependence of fold switching and its mechanism. We demonstrate that the stability of gsKaiB increases with temperature compared to fsKaiB and that the Q10 value for the gsKaiB [->] fsKaiB transition is nearly three times smaller than that for the reverse transition. Simulations and native-state hydrogen-deuterium exchange NMR experiments suggest that fold switching can involve both subglobally and near-globally unfolded intermediates. The simulations predict that the transition state for fold switching coincides with isomerization of conserved prolines in the most rapidly exchanging region, and we confirm experimentally that proline isomerization is a rate-limiting step for fold switching. We explore the implications of our results for temperature compensation, a hallmark of circadian clocks, through a kinetic model.

biochemistry↗

bioRxiv2024

Targeting protein tyrosine phosphatase non-receptor type 2 with a novel inhibitor for AML therapy

Acute myeloid leukemia (AML) is a fatal disease characterized by a bleak prognosis. For over four decades, treatment options for AML have been constrained to administering high-dose cytotoxic chemotherapy. However, the emergence of drug resistance and the resultant toxic side effects have created an urgent necessity for identifying novel therapeutic targets. In this study, non-receptor protein tyrosine phosphatase type 2 (PTPN2) is highly expressed in AML. Remarkably, knock down of PTPN2 expression markedly mitigated AML burden both in vitro and in vivo. Additionally, we unveiled the direct interaction between PTPN2 and C-MYC, establishing C-MYC as a direct acting substrate of PTPN2. Then, we performed a small-molecule compound screening to identify K73, a selective inhibitor of PTPN2. At the same time, K73 showed a good safety profile and exhibited strong activity against AML in vivo. In conclusion, we have pinpointed a considerable therapeutic potential in targeting PTPN2 for AML treatment and discovered a novel class of selective PTPN2 inhibitors suitable for AML therapy.

cancer biology↗

bioRxiv2024

Upregulated expression of ubiquitin ligase TRIM21 promotes PKM2 nuclear translocation and astrocyte activation in experimental autoimmune encephalomyelitis

Reactive astrocytes play critical roles in the occurrence of various neurological diseases such as multiple sclerosis. Activation of astrocytes is often accompanied by a glycolysis-dominant metabolic switch. However, the role and molecular mechanism of metabolic reprogramming in activation of astrocytes have not been clarified. Here, we found that PKM2, a notoriously known rate-limiting enzyme of glycolysis, displayed nuclear translocation in astrocytes of EAE (experimental autoimmune encephalomyelitis) mice, an animal model of multiple sclerosis. Prevention of PKM2 nuclear import by DASA-58 significantly reduced the activation of primary astrocytes, which was observed by decreased proliferation, glycolysis and secretion of inflammatory cytokines. Most importantly, we identified the ubiquitination-mediated regulation of PKM2 nuclear import by ubiquitin ligase TRIM21. TRIM21 interacted with PKM2, promoted its nuclear translocation and stimulated its nuclear activity to phosphorylate STAT3, NF-{kappa}B and interact with c-myc. Further single-cell RNA sequencing and immunofluorescence staining demonstrated that TRIM21 expression was upregulated in astrocytes of EAE. TRIM21 overexpressing in primary astrocytes enhanced PKM2-dependent glycolysis and proliferation, which could be reversed by DASA-58. Moreover, intracerebroventricular injection of a lentiviral vector to knockdown TRIM21 in astrocytes or intraperitoneal injection of TEPP-46, which inhibit the nuclear translocation of PKM2, effectively decreased disease severity, CNS inflammation and demyelination in EAE. Collectively, our study provides novel insights into the pathological function of nuclear glycolytic enzyme PKM2 and ubiquitination-mediated regulatory mechanism that are involved in astrocyte activation. Targeting this axis may be a potential therapeutic strategy for the treatment of astrocyte-involved neurological disease.

neuroscience↗

bioRxiv2024

Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally

The stability of functional brain network is maintained by homeostatic plasticity, which restores equilibrium following perturbation. As the initiation site of action potentials, the axon initial segment (AIS) of glutamatergic projection neurons (PyNs) undergoes dynamic adjustment that exerts powerful control over neuronal firing properties in response to changes in network states. Although AIS plasticity has been reported to be coupled with the changes of network activity, it is poorly understood whether it involves direct synaptic input to the AIS. Here we show that changes of GABAergic synaptic input to the AIS of cortical PyNs, specifically from chandelier cells (ChCs), are sufficient to drive homeostatic tuning of the AIS within 1-2 weeks, while those from parvalbumin-positive basket cells do not. This tuning is reflected in the morphology of the AIS, the expression level of voltage-gated sodium channels, and the intrinsic neuronal excitability of PyNs. Interestingly, the timing of AIS tuning in PyNs of the prefrontal cortex corresponds to the recovery of changes in social behavior caused by alterations of ChC synaptic transmission. Thus, homeostatic plasticity of the AIS at postsynaptic PyNs may counteract deficits elicited by imbalanced ChC presynaptic input. TeaserAxon initial segment dynamically responds to changes in local input from chandelier cells to prevent abnormal neuronal functions.

neuroscience↗