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Xue, M.

Publications and source records attributed to Xue, M..

At least 19 recordsLinked to original sources

SAIL: Sparse Autoencoders for Interpretable Alignment of Human Vision and Multimodal Large Language Models

Alignment between human high-level visual representations and those of multimodal large language models (MLLMs) offers a quantitative framework for understanding information processing in human vision. However, similarities between model and brain representations do not directly reveal the semantic content underlying their correspondence, as this content is difficult to isolate in entangled MLLM representations. Here, we introduce SAIL, an interpretable framework that formulates voxel interpretation as a multi-unit sparse semantic correspondence problem between MLLMs and human vision. First, we train unified cross-layer sparse autoencoders (SAEs) on MLLM representations of Natural Scenes Dataset images and captions, and align each brain voxel with multiple SAE units. Second, we quantify semantic similarity between their top-response image sets to map semantic alignment across the cortex. We project multiple semantic labels back onto the cortex to interpret the content of this alignment. Finally, we assess these correspondences using category responses measured in independent fLoc experiments. Compared with SAEs trained independently at each layer, SAIL exhibits lower redundancy in SAE unit response profiles and higher semantic alignment. We find that semantic alignment is organized along the human ventral visual pathway across the models and subjects examined. The projected labels reveal semantic preferences within canonical visual regions, while fLoc experiments show agreement between predicted and measured category response patterns. Exploratory analyses further reveal cortical distributions of action-related semantics consistent with established functional accounts of lateral occipitotemporal and posterior parietal cortex. Overall, SAIL provides an interpretable account of the semantic correspondences between MLLM representations and human visual responses.

neuroscience↗

Synaptic input-selective homeostasis safeguards developing cortical neurons toward setpoint activity

Homeostatic plasticity stabilizes brain function by maintaining neuronal activity around a setpoint. Although homeostatic mechanisms are well characterized in mature circuits, it remains unknown how developing neurons, which progress from near silence at birth to sustained activity, establish and safeguard their setpoint activity levels against perturbations. Here we show that activity setpoints are intrinsic properties of neuronal identity actively achieved by cell-autonomous, targeted synaptic remodeling during development. Cortical layer 2/3 pyramidal cells were sparsely silenced from their birth by overexpressing the inward-rectifier potassium channel Kir2.1 to chronically suppress their excitability. These Kir2.1-expressing neurons, however, progressively overcame this perturbation during postnatal development and ultimately reached the activity levels comparable to neighboring control neurons. This recovery was accompanied by enhanced synaptic excitation and reduced inhibition that did not follow the classical global multiplicative synaptic scaling. Instead, excitation from infragranular layers, rather than layer 4 and layer 2/3, was selectively strengthened through increasing quantal amplitudes and unsilencing silent synapses that required the insertion of GluA2-containing AMPA receptors. Inhibition recruited by excitatory inputs was selectively reduced at specific pathways. These results identify a synaptic input-selective homeostatic program enabling cortical neurons to reach activity setpoints, revealing a new mechanism contributing to neurodevelopmental robustness.

neuroscience↗

A highly Ca2+-permeable channelrhodopsin from the ancyromonad Nutomonas longa enables optogenetic control of Ca2+ signaling

Ca{superscript 2} is a ubiquitous regulator of cellular function, linking electrical activity to gene expression, secretion, metabolism, and synaptic plasticity. Yet, tools for its direct, time-resolved optical manipulation remain limited. Here, we report that NlCCR, a channelrhodopsin from Nutomonas longa, possesses high Ca{superscript 2} permeability, enabling precise optical control of Ca{superscript 2} signaling. Compared with CapChR2, the most potent engineered Ca{superscript 2}-conducting channelrhodopsin, NlCCR combines larger and faster photocurrents, higher Ca{superscript 2} permeability, weaker desensitization, and reduced inward rectification. Mutational analysis identified determinants of Ca{superscript 2} selectivity and further enhanced it by introducing carboxylate residues at the channels central gate. NlCCRs blue-shifted absorption (445 nm) minimized optical crosstalk with a red-shifted Ca{superscript 2} indicator, laying the groundwork for all-optical experiments. In mouse cortical pyramidal neurons, NlCCR enabled synaptic transmission independently of endogenous voltage-gated Ca{superscript 2} channels. These findings establish NlCCR as a broadly applicable tool for direct, temporally precise manipulation of Ca{superscript 2}-dependent signaling in living systems.

neuroscience↗

The HSV-1 immediate early protein ICP22 interacts with the human antisense function 1 protein to promote viral replication

Herpes simplex virus type 1 (HSV-1) is a common human pathogen that undergoes lytic replication in epithelial and other permissive cell types and can establish latency in peripheral neurons. ICP22 is a multifunctional HSV-1 immediate-early protein that localizes to the nucleus of infected cells; however, its interactions with host cellular factors remain incompletely understood. Here, ICP22 was demonstrated to interact with the human antisense function 1 protein (ASF1), including both ASF1a and ASF1b, in transfected cells and HSV-1-infected cells, respectively. ICP22 also colocalized with ASF1 in the nucleus. ICP22 amino acids 213 to 340 are important for the interaction of ICP22 with ASF1, whereas amino acids 37 to 153 of ASF1a and ASF1b are critical for their interactions with ICP22. Furthermore, ICP22 expression was associated with reduced ASF1-H3.1 co-immunoprecipitation under the tested conditions. ASF1 knockdown also reduced HSV-1-BAC-Luc luciferase output, indicating that ASF1 contributes to efficient infection-associated reporter activity in this study. Collectively, these results indicate that the interaction of HSV-1 ICP22 with ASF1 might help regulate the transcription of viral or cellular genes during HSV-1 infection.

microbiology↗

Stress granule sequestration of OXPHOS gene transcripts exacerbates glycolytic restriction

Stress granules (SGs) are dynamic organelles formed under cellular stress and they are generally regarded as protective entities. Meanwhile, their role in pathogenesis is becoming increasingly recognized, but the underlying mechanisms remain elusive due to the diverse nature of both stress types and biological contexts. Here we investigate SG dynamics and temporal changes in bulk and SG-associated transcriptomes under different regimens that inhibit glycolysis. We subject cells to either single assaults of glucose depletion (GD) or 2-deoxy-D-glucose addition (2DG) or a combined treatment (GD+2DG). We find that SGs formed under these conditions exhibit distinct properties, including eIF2 phosphorylation dependency, mRNA composition, and capacity to disassembly. Our results show that SGs induced by GD+2DG uniquely trap oxidative phosphorylation (OXPHOS) gene transcripts, leading to mitochondrial dysfunction. We provide evidence suggesting that the persistency of SGs formed under GD+2DG treatment is interwoven with mitochondrial dysfunction resulting in heightened apoptosis, effects that can also be recreated under single assaults when combined with mitochondrial inhibition. Our findings suggest that SG formation induced by inhibiting a single metabolic pathway can widen its impact in intensifying cellular metabolic stress under specific conditions, providing mechanistic insights into the paradoxical dual nature of SGs in stress response and pathology.

cell biology↗

Inhibiting RhoA Activation via GDP-state Stabilization to Relieve Heart Failure

High rates of heart failure (HF) morbidity and mortality have made targeting myocardial remodeling--particularly hypertrophy and fibrosis--a key therapeutic focus. RhoA, which regulates cytoskeletal reorganization and cell migration, plays a role in this process. However, RhoA has long been considered "undruggable", due to its strong binding to its endogenous substrates, GDP/GTP, and the lack of well-defined pockets for drug targeting. Here, we discovered a cryptic pocket proximate to GDP within RhoA and identified a natural product, AH001, binds here and interacts with GDP, stabilizing RhoAs interaction with its endogenous inhibitor, RhoGDI. AH001 reduced the downstream MRTFA nuclear translocation and downregulated fibrosis/hypertrophy proteins. Consequently, AH001 mitigated myocardial remodeling in multiple HF animal models, and in the 3D myocardial tissue model. Our findings highlight the therapeutic potential of inhibiting RhoA activation in myocardial remodeling, ultimately targeting HF, and offer a promising avenue for developing reversible inhibitors against undruggable GTPases.

pharmacology and toxicology↗

Single amino acid mutations in histone H3.3 illuminate the functional significance of H3K4 methylation in plants

Although numerous data have revealed correlations between histone modifications and chromatin activities such as transcription, proofs of their causal importance in gene expression regulation remain limited. Sequence variants within each histone family expand chromatin diversity and may carry specific modifications, further raising the question of how histone modifications coordinate with different variants. Here, we investigate the regulatory role of lysine 4 (K4) of Arabidopsis histone H3 by point mutating K4 in two major H3 variants, H3.1 and H3.3. K4 is essential for the function of H3.3 but not H3.1 in plant development. H3K4 methylation levels decrease drastically upon K4 mutation in H3.3, and the associated transcriptome changes are similar to those observed in a mutant lacking SDG2, a major enzyme responsible for depositing H3K4 trimethylation (H3K4me3). Moreover, H3.3K4 and SDG2 are required for de novo gene activation and RNA Pol II elongation. H3K4 methylation is preferentially accumulated on H3.3 compared to H3.1, likely due to the close association of the H3.3 deposition and H3K4 methylation machineries. Furthermore, we reveal the diverse impacts of K4 nearby residue mutations on H3K4 methylation and H3.3 function. Collectively, these findings suggest that H3.3 serves as a critical substrate for H3K4 methylation, which is important for gene expression regulation. In addition, our work highlights the potential of using plants as a platform to directly investigate the importance of histone amino acids and their modifications.

plant biology↗

EMMPRIN confers metabolic advantage for monocytes and macrophages to promote disease in a model of multiple sclerosis

Monocytes and monocyte-derived macrophages have important roles in the initiation and progression of multiple sclerosis (MS). These cells undergo metabolic reprogramming to generate immunophenotypes that promote leukocyte infiltration, axonal degeneration and demyelination, worsening MS pathology. The mechanisms that dictate metabolic programs in monocytes and macrophages in MS remain unclear. We previously reported that extracellular matrix metalloproteinase inducer (EMMPRIN, CD147), a glycoprotein that acts as a chaperone of monocarboxylate transporter 4 (MCT4), assisted with glycolysis-driven pro-inflammatory phenotype in macrophages in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Using newly-generated CCR2CreERT2:EMMPRINfl/fl (CCR2:EMMP) mice, we report that presymptomatic deletion of EMMPRIN in CCR2+ monocytes prevented or reduced clinical disability of EAE. This was correspondent with decreased infiltration of leukocytes into the CNS. Single cell RNA-seq of blood monocytes from EAE and proteomics analysis of macrophages from CCR2:EMMP-/- mice revealed significant alterations in metabolic programs, particularly reduced glycolysis and elevated mitochondrial electron transport and fatty acid oxidation, which were linked to their reduced pro-inflammatory traits. Our findings implicate EMMPRIN as a key regulator of metabolic pathways that exacerbate pro-inflammatory functions of monocytes in MS.

immunology↗

Synaptic alterations in pyramidal cells following genetic manipulation of neuronal excitability in monkey prefrontal cortex

In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have lower expression levels of activity-dependent genes and of genes involved in mitochondrial energy production. In concert, these findings from previous studies suggest that DLPFC L3PNs are hypoactive in schizophrenia, disrupting the patterns of activity that are crucial for working memory, which is impaired in the illness. However, whether lower PN activity produces alterations in inhibitory and/or excitatory synaptic strength has not been tested in the primate DLPFC. Here, we decreased PN excitability in rhesus monkey DLPFC in vivo using adeno-associated viral vectors (AAVs) to produce Cre recombinase-mediated overexpression of Kir2.1 channels, a genetic silencing tool that efficiently decreases neuronal excitability. In acute slices prepared from DLPFC 7-12 weeks post-AAV microinjections, Kir2.1-overexpressing PNs had a significantly reduced excitability largely attributable to highly specific effects of the AAV-encoded Kir2.1 channels. Moreover, recordings of synaptic currents showed that Kir2.1-overexpressing DLPFC PNs had reduced strength of excitatory synapses whereas inhibitory synaptic inputs were not affected. The decrease in excitatory synaptic strength was not associated with changes in dendritic spine number, suggesting that excitatory synapse quantity was unaltered in Kir2.1-overexpressing DLPFC PNs. These findings suggest that, in schizophrenia, the excitatory synapses on hypoactive L3PNs are weaker and thus might represent a substrate for novel therapeutic interventions. Significance StatementIn schizophrenia, dorsolateral prefrontal cortex (DLPFC) pyramidal neurons (PNs) have both transcriptional and structural alterations that suggest they are hypoactive. PN hypoactivity is thought to produce synaptic alterations in schizophrenia, however the effects of lower neuronal activity on synaptic function in primate DLPFC have not been examined. Here, we used, for the first time in primate neocortex, adeno-associated viral vectors (AAVs) to reduce PN excitability with Kir2.1 channel overexpression and tested if this manipulation altered the strength of synaptic inputs onto the Kir2.1-overexpressing PNs. Recordings in DLPFC slices showed that Kir2.1 overexpression depressed excitatory (but not inhibitory), synaptic currents, suggesting that, in schizophrenia, the hypoactivity of PNs might be exacerbated by reduced strength of the excitatory synapses they receive.

neuroscience↗

Structural insights into sphingosine 1-phosphate receptor 4 activation

S1PR4 is one of five subtypes of sphingosine 1-phosphate receptors (S1PRs) that regulate immune cell functioning, with functional distinctions to other subtypes. S1PR1-targeted modulators caused serious cardiac and vascular adverse effects because S1PR1 was expressed throughout the whole body. Since S1PR4 was only expressed in lung and lymphoid cells, S1PR4-targeted modulators might not trigger these side effects. However, the development of S1PR4-specific agonists is greatly hindered because of the lack of activated S1PR4 structure. Here, we resolved cryo-EM structures of activated S1PR4 and revealed the structural mechanism of ligand recognition, receptor activation, and Gi coupling. Our results offered structural templates for the development of selective S1PR4 agonists with improved safety profiles.

biochemistry↗

Polysaccharides from Balanophora harlandii Hook: Isolation, Characterization, and Anti-Inflammation Activities

Balanophora harlandii Hook (B. harlandii), a folk medicine, has been traditionally employed to treat traumatic bleeding, gastroenteritis, icteric hepatitis, hemorrhoids, and other conditions. In this work, polysaccharides with anti-inflammatory effects were extracted and purified from B. harlandii. The extraction conditions were optimized, and the properties of one purified neutral fraction, denoted as BHPs-W-S3, were analyzed. Gel permeation chromatography (GPC) was carried out to measure the molecular weight. The structure of BHPs-W-S3 was assessed based on monosaccharide composition analysis, Fourier transform infrared (FT-IR) spectroscopy, methylation analysis, and nuclear magnetic resonance (NMR) spectroscopy. BHPs-W-S3 has a molecular weight of 14.1 kDa, and its three main monosaccharides are glucose, galactose, and mannose with a molar ratio of 6.4:1.7:1.1. Its main chain consists of [->]6)--D-Glcp-(1[->], [->]4,6)--D-Glcp-(1[->], [->]6)-{beta}-D-Galp-(1[->], [->]3,6)-{beta}-D-Galp-(1[->], and it has branch chains at the O-4 and/or O-3 positions. In addition, in vitro experiments show that the polysaccharides from B. harlandi can decrease the phosphorylation level of p65 and IKB- in LPS-induced RAW264.7 cells to reduce the expression of the pro-inflammatory genes such as TNF-, IL-6, and IL-1{beta}. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/559774v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@17ccfeforg.highwire.dtl.DTLVardef@137726borg.highwire.dtl.DTLVardef@139100dorg.highwire.dtl.DTLVardef@14cce50_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

NGAL contributes to hemostasis and thrombosis by potentiating or suppressing coagulant or anticoagulant factors

Coagulation is related to inflammation, but the key pathways, especially innate immunity inflammatory response-coagulation, hemostasis, and thrombosis regulation is poorly understood and need to be further explored. In the current study, we showed that innate immunity inflammatory mediator neutrophil gelatinase-associated apolipoprotein (NGAL) which was upregulated in plasma of deep vein thrombosis patients interacted with and potentiated thrombin, kallikrein, FXIa, and FVIIa and suppressed antithrombin to induce coagulation, hemostasis, and thrombosis. Furthermore, NGAL can augment thrombin-induced platelet aggregation. In multiple mice hemostasis and thrombosis models, NGAL overexpression or intravenous administration promoted coagulation and hemostasis and aggravated thrombus, whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged both mice tail bleeding time and artery occlusion time to over 40 min, resembling uncontrollable bleeding and clotting disorder seen in Hemophilia mice. Furthermore, anti-NGAL monoclonal antibody treatment markedly reduced the formation of blood clots in a mouse-tail thrombosis model induced by carrageenan, which is linked to inflammation. Collectively, these findings suggest NGAL is a crucial coagulation regulator and mediates the crosstalk between innate immunity inflammation and coagulation, hemostasis, and thrombus, and provide new target and strategy for the development of innovative antithrombotic drugs.

biochemistry↗

Prominent elevation of extracellular matrix molecules in intracerebral hemorrhage

BackgroundIntracerebral hemorrhage (ICH) is the predominant type of hemorrhagic stroke with high mortality and disability. In other neurological conditions, the deposition of extracellular matrix (ECM) molecules is a prominent obstacle for regenerative processes and an enhancer of neuroinflammation. Whether ECM molecules alter in composition after ICH, and which ECM members may inhibit repair, remain unknown in hemorrhagic stroke. MethodsThe collagenase-induced ICH mouse model and an autopsied human ICH specimen were investigated for expression of ECM members by immunofluorescence microscopy. Confocal image z-stacks were analyzed with Imaris 3D to assess the association of immune cells and ECM molecules. Sections from a mouse model of multiple sclerosis were used as disease controls. Tissue culture was employed to examine the roles of ECM members on oligodendrocyte precursor cells (OPCs). ResultsAmongst the lectican chondroitin sulphate proteoglycan (CSPG) members, neurocan but not aggrecan, versican-V1 and versican-V2 was prominently expressed in perihematomal tissue and lesion core compared to the contralateral area in murine ICH. Fibrinogen, fibronectin and heparan sulphate proteoglycan (HSPG) were also elevated after murine ICH while thrombospondin was not. Confocal microscopy with Imaris 3D rendering co-localized neurocan, fibrinogen, fibronectin and HSPG molecules to Iba1+ microglia/macrophages or GFAP+ astrocytes. Marked differentiation from the multiple sclerosis model was observed, the latter with high versican-V1 and negligible neurocan. In culture, purified neurocan inhibited adhesion and process outgrowth of OPCs, which are early steps in myelination in vivo. The prominent expression of neurocan in murine ICH was corroborated in human ICH sections. ConclusionICH caused distinct alterations in ECM molecules. Amongst CSPG members, neurocan was selectively upregulated in both murine and human ICH. In tissue culture, neurocan impeded the properties of oligodendrocyte lineage cells. Alterations to the ECM in ICH may adversely affect reparative outcomes after stroke. What is already known on this topic - CSPGs are known to be elevated in multiple sclerosis and intraventricular hemorrhage, where they act as inhibitors of repair by hindering remyelination and axonal regeneration, as well as promoting neuroinflammation. However, there is currently no literature available regarding the role of CSPGs in ICH. What this study adds - Our findings demonstrate the elevation of specific ECM molecules, particularly neurocan, in murine and human ICH. These matrix molecules will likely affect subsequent reparative processes such as remyelination, as suggested by the result that purified neurocan impairs the process outgrowth and maturation of oligodendrocyte precursor cells. How this study might affect research, practice or policy - The targeting of ECM molecules represents a promising strategy to promote remyelination and control neuroinflammation, with the potential to improve prognosis following ICH.

neuroscience↗

DDHD2 interacts with STXBP1 to mediate long-term memory via the generation of myristic acid

The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brains lipid landscape remain largely unexplored. Saturated FFAs, particularly myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the DDHD2 isoform of PLA1 in mice reduced memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits, and markedly reduced saturated FFAs across the brain. DDHD2 was shown to bind to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1+/- mouse model of STXBP1 encephalopathy that is also associated with intellectual disability and motor dysfunction, we show that STXBP1 controls the targeting of DDHD2 to the plasma membrane and the generation of saturated FFAs in the brain. Our findings suggest key roles for DDHD2 and STXBP1 in the lipid metabolism underlying synaptic plasticity, learning and memory.

neuroscience↗

A maize lipid droplet-associated protein is modulated by a virus to promote viral multiplication and infection

Pathogen infection induces massive reprogramming of host primary metabolism. Lipid and fatty acid metabolism is generally disrupted by pathogens and co-opted for their proliferation. Lipid droplets (LDs) that play important roles in regulating cellular lipid metabolism are utilized by a variety of pathogens in mammalian cells. However, the function of LDs during pathogenic infection in plants remains unknown. We show here that infection by rice black streaked dwarf virus (RBSDV) affects the lipid metabolism of maize, which causes elevated accumulation of C18 polyunsaturated fatty acids (PUFAs) leading to viral proliferation and symptom development. Overexpression of one of the two novel LD-associated proteins (LDAPs) of maize (ZmLDAP1 and ZmLDAP2) induces LD clustering. The core capsid protein P8 of RBSDV interacts with ZmLDAP2 and prevents its degradation through the ubiquitin-proteasome system mediated by a UBX domain-containing protein, PUX10. In addition, silencing of the ZmLDAP2 down-regulates expression of fatty acid desaturase genes in maize, leading to a decrease in C18 PUFAs levels and suppression of RBSDV accumulation. Our findings reveal that the plant virus recruits LDAP to regulate cellular fatty acid metabolism to promote viral multiplication and infection. These results expand the knowledge of the LD functions and viral infection mechanism in plants. One Sentence SummaryRice black streaked dwarf virus recruits a lipid droplet-associated protein to regulate cellular fatty acid metabolism for promoting viral multiplication and infection.

pathology↗

An e-cigarette aerosol generation, animal exposure and toxicants quantification system to characterize in vivo nicotine kinetics in arterial and venous blood

The increasing e-cigarette use worldwide presents an urgent need to characterize their nicotine delivery property, brain stimulation and potential long-term health effects. We constructed an end-to-end system enabling combustible-cigarette (c-cigarette) and e-cigarette aerosol generation, animal exposure, and effect assessment. The system consists of (1) a 10-channel aerosol generator resembling human smoking/vaping scenarios, (2) nose-only and whole-body exposure chambers suitable for long- or short-duration studies, (3) a lab protocol for animal exposure and collecting arterial and venous blood <1 minute after the exposure, and (4) chromatograph and mass spectrometry to quantify nicotine concentrations in aerosol and biospecimens. We applied the system in a proof-of-principle study characterizing in vivo nicotine delivery after e-cigarette aerosol inhalation. Groups of Sprague-Dawley rats were exposed to e-cigarette aerosols for 1, 2 and 4 minutes, respectively. Arterial and venous blood samples were collected immediately after the exposure. We also directly compared nose-only and whole-body exposure approaches. After nose-only e-cigarette aerosol exposure, the nicotine concentration in arterial blood was substantially higher (11.32 ng/mL in average) than in veins. Similar arterio-venous concentration difference was observed in whole-body exposure experiments. In summary, we described a complete system ideal for e- and c-cigarette in vivo nicotine kinetics and long-term health research. Our findings highlight arterial blood as the suitable bio-specimen for e-cigarette nicotine delivery studies. HighlightO_LIWe constructed a combustible- and e-cigarette aerosol generation - exposure - effect assessment system resembling real world human smoking/vaping scenarios. C_LIO_LIProof-of-principle study characterized in vivo nicotine delivery from e-cigarette aerosol to arterial and venous blood at high temporal resolution. C_LIO_LIAfter exposure, the nicotine concentration was substantially higher (11.32 ng/mL) in arterial blood than in veins. C_LIO_LIOur results suggest arterial blood as the suitable bio-specimen to study nicotine delivery and brain stimulation. C_LI

pharmacology and toxicology↗

Cell-type specific deletions of Neuroligin 2 reveal a vital role of synaptic excitation-inhibition balance

Synaptic excitation (E) and inhibition (I) stay relatively proportional to each other over different spatiotemporal scales, orchestrating neuronal activity in the brain. This proportionality, referred to as E-I balance, is thought to be critical for neuronal functions because its disruption was observed in many neurological disorders. However, the causal evidence demonstrating its significance is scarce. Here we show that deleting Neuroligin-2 (Nlgn2), a postsynaptic adhesion molecule at inhibitory synapses, from mouse glutamatergic or GABAergic neurons reduces inhibition cell-autonomously without affecting excitation, thereby disrupting E-I balance and causing lethality. In contrast, deleting Nlgn2 constitutively or simultaneously from both glutamatergic and GABAergic neurons results in viable mice. A neural network model shows that reducing inhibition in either neuronal type is detrimental to network activity, but in both types partially re-establishes E-I balance and activity. Together, our results provide evidence for an essential role of E-I balance in brain functions and organism survival.

neuroscience↗

Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here we report that reducing Ube3a-ATS by antisense oligonucleotides in juvenile or adult maternal Ube3a knockout mice rescues the abnormal electroencephalogram rhythms and sleep disturbance, two prominent clinical features of Angelman syndrome. Importantly, the degree of phenotypic improvement correlates with the increase of Ube3a protein levels. These results indicate that the therapeutic window of genetic therapies for Angelman syndrome is broader than previously thought, and electroencephalogram power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies.

neuroscience↗