Social circuits and their dysfunction in autism spectrum disorder

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(8), P. 3194 - 3206

Published: Aug. 1, 2023

Social behaviors, how individuals act cooperatively and competitively with conspecifics, are widely seen across species. Rodents display various social many different behavioral paradigms have been used for investigating their neural circuit bases. behavior is highly vulnerable to brain network dysfunction caused by neurological neuropsychiatric conditions such as autism spectrum disorders (ASDs). Studying mouse models of ASD provides a promising avenue toward elucidating mechanisms abnormal potential therapeutic targets treatment. In this review, we outline recent progress key findings on underlying behavior, particular emphasis rodent studies that monitor manipulate the activity specific circuits using modern systems neuroscience approaches. mediated distributed brain-wide among major cortical (e.g., medial prefrontal cortex (mPFC), anterior cingulate cortex, insular (IC)) subcortical nucleus accumbens, basolateral amygdala (BLA), ventral tegmental area) structures, influenced multiple neuromodulatory oxytocin, dopamine, serotonin). We particularly draw special attention IC unique area mediates multisensory integration, encoding ongoing interaction, decision-making, emotion, empathy. Additionally, synthesis demonstrates dysfunctions in mPFC-BLA circuitry neuromodulation prominent. Pharmacological rescues local or systemic oral) administration drugs provided valuable clues developing new agents ASD. Future efforts technological advances will push forward next frontiers field, elucidation inter-brain dynamics during real virtual interactions, establishment circuit-based therapy affecting functions.

Language: Английский

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The role of the prefrontal cortex in social interactions of animal models and the implications for autism spectrum disorder

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 14

Published: June 20, 2023

Social interaction is a complex behavior which requires the individual to integrate various internal processes, such as social motivation, recognition, salience, reward, and emotional state, well external cues informing of others' behavior, state rank. This phenotype susceptible disruption in humans affected by neurodevelopmental psychiatric disorders, including autism spectrum disorder (ASD). Multiple pieces convergent evidence collected from studies rodents suggest that prefrontal cortex (PFC) plays pivotal role interactions, serving hub for affiliation, empathy, hierarchy. Indeed, PFC circuitry results deficits symptomatic ASD. Here, we review this describe ethologically relevant tasks could be employed with rodent models study interactions. We also discuss linking pathologies associated Finally, address specific questions regarding mechanisms may result atypical interactions models, future should address.

Language: Английский

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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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Restoration of excitation/inhibition balance enhances neuronal signal-to-noise ratio and rescues social deficits in autism-associatedScn2a-deficiency

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Social behavior is critical for survival and adaptation, which profoundly disrupted in autism spectrum disorders (ASD). withdrawal due to information overload was often described ASD, it suspected that increased basal noise, i.e., excessive background neuronal activities the brain could be a disease mechanism. However, experimental test of this hypothesis limited. Loss-of-function mutations (deficiency) SCN2A , encodes voltage-gated sodium channel Na V 1.2, have been revealed as leading monogenic cause profound ASD. Here, we Scn2a deficiency results robust multifaceted social impairments mice. -deficient neurons displayed an excitation-inhibition (E/I) ratio, contributing elevated noise diminished signal-to-noise ratio (SNR) during interactions. Notably, restoration expression adulthood able rescue both SNR deficits. By balancing E/I reducing firing, FDA-approved GABA A receptor-positive allosteric modulator improves sociability mice normalizes translationally relevant human organoids carrying autism-associated nonsense mutation. Collectively, our findings role 1.2 regulation behaviors, identified molecular, cellular, circuitry mechanisms underlying -associated disorders. leads pronounced deficits overall enhanced activity, impaired ratio. Both are reversible through adulthood. Targeted striatum-projecting rescues impairments. transmission reduced mouse organoid models deficiency, acute systemic administration modulators restores sociability. Graphical abstract: Severe predominate decrease with SNR, adult 1.2-deficient

Language: Английский

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Shank postsynaptic scaffolding proteins in autism spectrum disorder: Mouse models and their dysfunctions in behaviors, synapses, and molecules

Pharmacological Research, Journal Year: 2022, Volume and Issue: 182, P. 106340 - 106340

Published: July 2, 2022

Postsynaptic scaffolding proteins, which are major components of the postsynaptic density (PSD) at excitatory synapses, include Shank, PSD-95, A-kinase anchoring protein, Homer, and SAP90/PSD-95-associated protein families play crucial roles in synaptic structure, signaling, functions. Several genetic studies have indicated that proteins contribute to etiology various psychiatric disorders, including neurodevelopmental disorders. Indeed, mice with mutations or deletions specific genes encoding display alterations behavioral phenotypes relevant Here, we review recent on mutant mouse models Shank associated autism spectrum disorder, a discuss future directions therapeutic strategies for treatment disorder.

Language: Английский

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Immune activation during pregnancy exacerbates ASD-related alterations in Shank3-deficient mice

Molecular Autism, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 5, 2023

Autism spectrum disorder (ASD) is mainly characterized by deficits in social interaction and communication repetitive behaviors. Known causes of ASD are mutations certain risk genes like the postsynaptic protein SHANK3 environmental factors including prenatal infections.

Language: Английский

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Bridging the translational gap: what can synaptopathies tell us about autism?

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: June 27, 2023

Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved biology. Synaptopathies are commonly developmental delay may be range neuropsychiatric outcomes. Altered biology suggested by both preclinical studies based evidence differences early brain structural development altered glutamatergic GABAergic neurotransmission potentially perturbing excitatory inhibitory balance. This review focusses NRXN-NLGN-SHANK pathway, assembly, trans-synaptic signalling, functioning. We provide an overview insights from pathway. Concentrating NRXN1 deletion SHANK3 mutations, we discuss emerging understanding electrophysiology induced pluripotent stem cells (iPSC) models derived individuals neuroimaging behavioural findings animal Nrxn1 Shank3 key regarding features, phenotypes human synaptopathies. The identification molecular-based biomarkers aims advance targeted therapeutic treatments. However, it remains challenging translate iPSC interpret features. existing challenges synaptopathy research, potential solutions align methodologies across research. Bridging translational gap between will necessary understand biological mechanisms, identify therapies, ultimately progress towards personalised approaches for complex such as autism.

Language: Английский

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Medial prefrontal cortex circuitry and social behaviour in autism

Neuropharmacology, Journal Year: 2024, Volume and Issue: 260, P. 110101 - 110101

Published: Aug. 14, 2024

Language: Английский

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Prefrontal Interneurons: Populations, Pathways, and Plasticity Supporting Typical and Disordered Cognition in Rodent Models

Journal of Neuroscience, Journal Year: 2022, Volume and Issue: 42(45), P. 8468 - 8476

Published: Nov. 9, 2022

Prefrontal cortex (PFC) inhibitory microcircuits regulate the gain and timing of pyramidal neuron firing, coordinate neural ensemble interactions, gate local long-range communication to support adaptive cognition contextually tuned behavior. Accordingly, perturbations PFC are thought underlie dysregulated behavior in numerous psychiatric diseases relevant animal models. This review, based on a Mini-Symposium presented at 2022 Society for Neuroscience Meeting, highlights recent studies providing novel insights into: (1) discrete medial (mPFC) interneuron populations mouse brain; (2) mPFC connections with, regulation of, afferents; (3) circuit-specific plasticity interneurons. The contributions such populations, pathways, rodent discussed context stress, reward, motivational conflict, genetic mutations disease.

Language: Английский

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Embryonic mercury exposure in zebrafish: Alteration of metabolites and gene expression, related to visual and behavioral impairments

Ecotoxicology and Environmental Safety, Journal Year: 2023, Volume and Issue: 256, P. 114862 - 114862

Published: March 31, 2023

The widespread presence of mercury, a heavy metal found in the environment and used numerous industries domestic, raises concerns about its potential impact on human health. Nevertheless, adverse effects this environmental toxicant at low concentrations are often underestimated. There emerging studies showing that accumulation mercury eye may contribute to visual impairment comorbidity between autism spectrum disorders (ASD) trait impairment. However, underlying mechanism humans rodents is challenging. In response issue, zebrafish larvae with cone-dominated retinal system were exposed 100 nM chloride (HgCl2), according our previous study, followed by light-dark stimulation, social assay, color preference examine functionality relation ASD-like behavior. Exposure embryos HgCl2 from gastrulation hatching increased locomotor activity dark, reduced shoaling exploratory behavior, impaired preference. Defects microridges as first barrier serve primary tools for toxicity affecting vision. Depletion polyunsaturated fatty acids (PUFAs), linoleic acid, arachidonic acid (ARA), alpha-linoleic docosahexaenoic (DHA), stearic L-phenylalanine, isoleucine, L-lysine, N-acetylputrescine, along increase gamma-aminobutyric (GABA), sphingosine-1-phosphate, citrulline assayed liquid chromatography-mass spectrometry (LC-MS) suggest these metabolites biomarkers impairments affect vision Although suppression adsl, shank3a, tsc1b, nrxn1a gene expression was observed, among tsc1b showed more positive correlation ASD. Collectively, results new insights into possible give rise visual, cognitive, deficits zebrafish.

Language: Английский

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