Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 6, 2025

Autism spectrum disorder (ASD) is a neurodevelopmental disability condition arising from combination of genetic and environmental factors. Despite the blood-brain barrier (BBB) serving as crucial gatekeeper, conveying influences into brain parenchyma, contributions BBB in ASD pathogenesis remain largely uncharted. Here we report that SHANK3, an ASD-risk gene, expresses BBB-forming endothelial cells (BECs) regulates tight junctional (TJ) integrity essential for BBB's function. Endothelium-specific Shank3 (eShank3) knockout (KO) neonatal mice exhibit male-specific BBB-hyperpermeability, reduced neuronal excitability, impaired ultra-sonic communications. Although permeability restored during adult age, male mutant display excitability sociability. Further analysis reveals BBB-hyperpermeability attributed to β-Catenin imbalance triggered by eShank3-KO. These findings highlight pathogenic mechanism stemming Shank3, emphasizing significance BECs potential therapeutic target ASD. This study SHANK3 deficiency disrupts function period through imbalance, leading ASD-related behavioral abnormalities.

Language: Английский

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Activation of the CA2-ventral CA1 pathway reverses social discrimination dysfunction in Shank3B knockout mice

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 29, 2023

Mutation or deletion of the SHANK3 gene, which encodes a synaptic scaffolding protein, is linked to autism spectrum disorder and Phelan-McDermid syndrome, conditions associated with social memory impairments. Shank3B knockout mice also exhibit deficits. The CA2 region hippocampus integrates numerous inputs sends major output ventral CA1 (vCA1). Despite finding few differences in excitatory afferents mice, we found that activation neurons as well CA2-vCA1 pathway restored recognition function wildtype levels. vCA1 neuronal oscillations have been memory, but observed no these measures between mice. However, enhanced theta power concurrent behavioral improvements. These findings suggest stimulating adult circuitry mouse model neurodevelopmental impairments can invoke latent function.

Language: Английский

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Developmental cascades between insistence on sameness behaviour and anxiety symptoms in autism spectrum disorder

European Child & Adolescent Psychiatry, Journal Year: 2022, Volume and Issue: 32(11), P. 2109 - 2118

Published: July 24, 2022

Language: Английский

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Hippocampal Engrams Generate Variable Behavioral Responses and Brain-Wide Network States

Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 44(2), P. e0340232023 - e0340232023

Published: Nov. 28, 2023

Freezing is a defensive behavior commonly examined during hippocampal-mediated fear engram reactivation. How these cellular populations engage the brain and modulate freezing across varying environmental demands unclear. To address this, we optogenetically reactivated in dentate gyrus subregion of hippocampus three distinct contexts male mice. We found that there were differential amounts light-induced depending on size context which reactivation occurred: mice demonstrated robust most spatially restricted but not largest. then utilized graph theoretical analyses to identify brain-wide alterations cFos expression smallest largest contexts. Our manipulations induced positive interregional correlations observed control conditions. Additionally, regions spanning putative “fear” “defense” systems recruited as hub networks. Lastly, compared network generated from small with natural memory retrieval network. Here, shared characteristics such modular composition regions. By identifying manipulating circuits supporting function, well their corresponding activity patterns, it thereby possible resolve systems-level biological mechanisms mediating memory's capacity behavioral states.

Language: Английский

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A systematic review of the pain-related emotional and cognitive impairments in chronic inflammatory pain induced by CFA injection and its mechanism

IBRO Neuroscience Reports, Journal Year: 2025, Volume and Issue: 18, P. 414 - 431

Published: Feb. 27, 2025

Language: Английский

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Not just for bonding: Nucleus accumbens oxytocin receptors facilitate huddling with strangers and feeding in male spiny mice

Psychoneuroendocrinology, Journal Year: 2025, Volume and Issue: unknown, P. 107496 - 107496

Published: May 1, 2025

Language: Английский

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A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autism

EBioMedicine, Journal Year: 2023, Volume and Issue: 91, P. 104565 - 104565

Published: April 22, 2023

Language: Английский

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Mitochondrial transplantation confers protection against the effects of ischemic stroke by repressing microglial pyroptosis and promoting neurogenesis

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 19(6), P. 1325 - 1335

Published: Sept. 22, 2023

Abstract JOURNAL/nrgr/04.03/01300535-202406000-00037/inline-graphic1/v/2023-10-30T152229Z/r/image-tiff Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury. Autologous mitochondrial transplantation is also beneficial pediatric patients with cardiac Thus, exogenous may be promising therapeutic approach for ischemic disease. To explore neuroprotective effect determine underlying mechanism stroke, this study we established photo-thrombosis-induced mouse focal ischemia administered freshly isolated via tail vein or injury site ( situ ). Animal behavior tests, immunofluorescence staining, 2,3,5-triphenyltetrazolium chloride (TTC) mRNA-seq, western blotting were used assess anxiety memory, cortical infarct area, pyroptosis, neurogenesis, respectively. Using bioinformatics analysis, blotting, co-immunoprecipitation, mass spectroscopy, identified S100 calcium binding protein A9 (S100A9) as potential regulator function determined its possible interacting proteins. Interactions between endogenous mitochondria, well on recipient microglia, assessed vitro . Our data showed that: (1) markedly reduced mortality improved emotional cognitive function, reducing inhibiting promoting neurogenesis; (2) microglial expression S100A9 was increased by regulated function; (3) , enhanced redox stress, polarization pyroptosis fusing mitochondria; (4) promoted internalization thereby amplifying their pro-proliferation anti-inflammatory effects. Taken together, our findings show that protects against deleterious effects stroke suppressing plays vital role mitochondria.

Language: Английский

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Comparison of predictive validity of two autism spectrum disorder rat models: Behavioural investigations

NeuroToxicology, Journal Year: 2024, Volume and Issue: 103, P. 39 - 49

Published: May 17, 2024

Language: Английский

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Mapping the Behavioral Signatures of Shank3b Mice in Both Sexes

Neuroscience Bulletin, Journal Year: 2024, Volume and Issue: 40(9), P. 1299 - 1314

Published: June 20, 2024

Abstract Autism spectrum disorders (ASD) are characterized by social and repetitive abnormalities. Although the ASD mouse model with Shank3b mutations is widely used in research, behavioral phenotype of this has not been fully elucidated. Here, a 3D-motion capture system linear discriminant analysis were to comprehensively record analyze patterns male female mutant mice. It was found that both sexes replicated core accompanied symptoms ASD, significant sex differences. Further, heterozygous knockout mice exhibited distinct autistic behaviors, significantly different from those observed wild type homozygous groups. Our findings provide evidence for inclusion experimental approaches efficiently characterize transgenic models, which more clinically relevant studies.

Language: Английский

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