GABA_Breceptor modulation of visual sensory processing in adults with and without autism spectrum disorder

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(626)

Published: Jan. 5, 2022

Differences in GABAergic function are critical to autistic visual sensory neurobiology and can be modulated by targeting GABA B .

Language: Английский

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Neural circuit pathology driven by Shank3 mutation disrupts social behaviors

Cell Reports, Journal Year: 2022, Volume and Issue: 39(10), P. 110906 - 110906

Published: June 1, 2022

Dysfunctional sociability is a core symptom in autism spectrum disorder (ASD) that may arise from neural-network dysconnectivity between multiple brain regions. However, pathogenic mechanisms underlying social dysfunction are largely unknown. Here, we demonstrate circuit-selective mutation (ctMUT) of ASD-risk Shank3 gene within unidirectional projection the prefrontal cortex to basolateral amygdala alters spine morphology and excitatory-inhibitory balance circuit. ctMUT mice show reduced as well elevated neural activity its amplitude variability, which consistent with neuroimaging results human ASD patients. Moreover, circuit hyper-activity disrupts temporal correlation socially tuned neurons events interactions. Finally, optogenetic activation wild-type partially recapitulates mice, while inhibition rescues behavior. Collectively, these highlight circuit-level mechanism drives dysfunction.

Language: Английский

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Reduced excitatory neuron activity and interneuron-type-specific deficits in a mouse model of Alzheimer’s disease

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Dec. 2, 2022

Abstract Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive decline. These impairments correlate with early alterations in neuronal network activity AD patients. Disruptions the of individual neurons have been reported mouse models amyloidosis. However, impact amyloid pathology on spontaneous distinct types remains unexplored vivo. Here we use vivo calcium imaging multiphoton microscopy to monitor compare excitatory two inhibitory interneurons cortices APP/PS1 control mice under isoflurane anesthesia. We also determine relationship between accumulation deficits mice. show that somatostatin-expressing (SOM) are hyperactive, while parvalbumin-expressing hypoactive Only SOM interneuron hyperactivity correlated proximity plaque. were accompanied decreased neuron Our study identifies cell-specific firing driven pathology. findings highlight importance addressing complexity neuron-specific ameliorate circuit dysfunction disease.

Language: Английский

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Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders

Annual Review of Genetics, Journal Year: 2022, Volume and Issue: 56(1), P. 391 - 422

Published: Sept. 3, 2022

Recent advances in genomics have revealed a wide spectrum of genetic variants associated with neurodevelopmental disorders at an unprecedented scale. An increasing number studies consistently identified mutations-both inherited and de novo-impacting the function specific brain circuits. This suggests that, during development, alterations distinct neural circuits, cell types, or broad regulatory pathways ultimately shaping synapses might be dysfunctional process underlying these disorders. Here, we review findings from human animal model research to provide comprehensive description synaptic circuit mechanisms implicated We discuss how connections commonly disrupted different cognition behaviors emerging imbalances neuronal Moreover, new approaches that been shown restore mitigate processes critical windows development. Considering heterogeneity disorders, also highlight recent progress developing improved clinical biomarkers strategies will help identify novel therapeutic compounds opportunities for early intervention.

Language: Английский

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Interneuron development and dysfunction

FEBS Journal, Journal Year: 2021, Volume and Issue: 289(8), P. 2318 - 2336

Published: April 12, 2021

Understanding excitation and inhibition balance in the brain begins with tale of two basic types neurons, glutamatergic projection neurons GABAergic interneurons. The diversity cortical interneurons is contributed by multiple origins ventral forebrain, various tangential migration routes, complicated regulations intrinsic factors, extrinsic signals, activities. Abnormalities interneuron development lead to dysfunction inhibitory circuits, which are highly associated neurodevelopmental disorders including schizophrenia, autism spectrum disorders, intellectual disability. In this review, we mainly discuss recent findings on related dysfunction.

Language: Английский

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Abnormal whisker-dependent behaviors and altered cortico-hippocampal connectivity in Shank3b−/− mice

Cerebral Cortex, Journal Year: 2021, Volume and Issue: 32(14), P. 3042 - 3056

Published: Oct. 8, 2021

Abstract Abnormal tactile response is an integral feature of Autism Spectrum Disorders (ASDs), and hypo-responsiveness to stimuli often associated with the severity ASDs core symptoms. Patients Phelan-McDermid syndrome (PMS), caused by mutations in SHANK3 gene, show ASD-like symptoms aberrant responses. The neural underpinnings these abnormalities are still poorly understood. Here we investigated, Shank3b−/− adult mice, substrates whisker-guided behaviors, a key component rodents’ interaction surrounding environment. We assessed whisker-dependent behaviors mice age-matched controls, using textured novel object recognition (tNORT) whisker nuisance (WN) test. showed deficits texture discrimination tNORT behavioral repetitive stimulation WN. Sensory was accompanied significantly reduced activation primary somatosensory cortex (S1) hippocampus, as measured c-fos mRNA induction, proxy neuronal activity following stimulation. Moreover, resting-state fMRI S1-hippocampal connectivity Shank3b mutants, absence altered between S1 other areas. Impaired crosstalk hippocampus might underlie hypo-reactivity cues, highlighting potentially generalizable dysfunction ASD.

Language: Английский

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Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome

Biological Psychiatry, Journal Year: 2021, Volume and Issue: 90(11), P. 742 - 755

Published: June 7, 2021

BackgroundMutations in the X-linked gene DDX3X account for approximately 2% of intellectual disability females, often comorbid with behavioral problems, motor deficits, and brain malformations. encodes an RNA helicase emerging functions corticogenesis synaptogenesis.MethodsWe generated a Ddx3x haploinsufficient mouse (Ddx3x+/− females) construct validity loss-of-function mutations. We used standardized batteries to assess developmental milestones adult behaviors, as well magnetic resonance imaging immunostaining cortical projection neurons capture early postnatal changes development.ResultsDdx3x+/− females showed physical, sensory, delays that evolved into anomalies adulthood, including hyperactivity, anxiety-like cognitive impairments specific tasks (e.g., contextual fear memory but not novel object recognition memory), deficits. Motor function declined age if mice were previously exposed training. Developmental associated reduction volume, some regions cortex amygdala) disproportionally affected. Cortical thinning was accompanied by defective lamination, indicating regulates balance glutamatergic developing cortex.ConclusionsThese data shed new light on mechanisms driving syndrome support face this preclinical model.

Language: Английский

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Absence of familiarity triggers hallmarks of autism in mouse model through aberrant tail-of-striatum and prelimbic cortex signaling

Neuron, Journal Year: 2022, Volume and Issue: 110(9), P. 1468 - 1482.e5

Published: Feb. 25, 2022

Autism spectrum disorder (ASD) involves genetic and environmental components. The underlying circuit mechanisms are unclear, but behaviorally, aversion toward unfamiliarity, a hallmark of autism, might be involved. Here, we show that in Shank3ΔC/ΔC ASD model mice, exposure to novel environments lacking familiar features produces long-lasting failure engage repetitive behaviors upon re-exposure. Inclusion at first context prevented enhanced dopamine transients tail striatum (TS) restored context-specific control engagement wild-type levels mice. Engagement re-exposure depended on the activity prelimbic cortex (PreL)-to-TS projection neurons mice was by chemogenetic activation PreL→TS neurons. Environmental enrichment ASD-like phenotypes obviating dependence activity. Therefore, experience has key role triggering genetically predisposed behavioral therapies involving familiarity prevent emergence phenotypes.

Language: Английский

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Excitatory and Inhibitory Synaptic Imbalance Caused by Brain-Derived Neurotrophic Factor Deficits During Development in a Valproic Acid Mouse Model of Autism

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: April 6, 2022

Environmental factors, such as medication during pregnancy, are one of the major causes autism spectrum disorder (ASD). Valproic acid (VPA) intake pregnancy has been reported to dramatically elevate risk in offspring. Recently, researchers have proposed that VPA exposure could induce excitatory or inhibitory synaptic dysfunction. However, it remains be determined whether and how alterations excitatory/inhibitory (E/I) balance contribute VPA-induced ASD a mouse model. In present study, we explored changes E/I different developmental periods We found typical markers pre- postsynaptic function involved markedly decreased development, reflecting difficulties development plasticity VPA-exposed mice. The expression brain-derived neurotrophic factor (BDNF), neurotrophin promotes formation maturation glutamatergic GABAergic synapses postnatal was severely reduced group. Treatment with exogenous BDNF critical imbalance period rescued functions autism-like behaviors, social defects. With these results, experimentally showed dysfunction model might caused by stemming from deficits stage.

Language: Английский

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Aberrant causal inference and presence of a compensatory mechanism in autism spectrum disorder

eLife, Journal Year: 2022, Volume and Issue: 11

Published: May 17, 2022

Autism spectrum disorder (ASD) is characterized by a panoply of social, communicative, and sensory anomalies. As such, central goal computational psychiatry to ascribe the heterogenous phenotypes observed in ASD limited set canonical computations that may have gone awry disorder. Here, we posit causal inference - process inferring structure linking signals hidden world causes as one such computation. We show audio-visual integration intact line with optimal models cue combination, yet multisensory behavior anomalous because this group operates under an internal model favoring (vs. segregation). Paradoxically, during explicit reports common cause across spatial or temporal disparities, individuals were less not more likely report cause, particularly at small disparities. Formal fitting revealed differences both prior probability for (p-common) choice biases, which are dissociable implicit but tasks. Together, pattern results suggests (i) different attributing relative neurotypical given identical cues, (ii) presence compensatory mechanism ASD, these putatively having learned compensate their bias integrate reports.

Language: Английский

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