A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(1), P. 341 - 353

Published: Oct. 3, 2022

Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks a range neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis our current psychiatric diagnostic classification system recognition an identifiable, highly penetrant risk factor in proportion patients ASD or SSD? Second, what be learned from studies individuals SSD who share common basis? And third, accounts for observed variable penetrance pleiotropy neuropsychiatric phenotypes same variant? In this review, focus on findings clinical preclinical 22q11.2 deletion syndrome (22q11DS). particular variant not only one most among list known variants, but also benefits relatively long research history. Consequently, 22q11DS appealing model as it allows us to: (1) elucidate specific genotype-phenotype associations, (2) prospectively study behaviorally defined classifications, such SSD, context known, well-characterized basis, (3) mechanisms underpinning pleiotropy, phenomena far-reaching ramifications practice. We discuss animal vitro relate to observations human help factors, genetic, environmental, stochastic, impact expression 22q11DS, may inform underlying general population. conclude priorities field, which pave way novel therapeutics.

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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iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 27, 2024

PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and distinct craniofacial abnormalities resulting from de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). known to have functions the endosomal pathway nucleus, but how affects developing neurons not fully understood. Here we differentiated stem cells towards neuronal models including cortical organoids investigate impact of syndrome-causing on neurodevelopment. While few deleterious effects were detected

Language: Английский

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Hypnotic treatment improves sleep architecture and EEG disruptions and rescues memory deficits in a mouse model of fragile X syndrome

Cell Reports, Journal Year: 2024, Volume and Issue: 43(6), P. 114266 - 114266

Published: May 23, 2024

Fragile X syndrome (FXS) is associated with disrupted cognition and sleep abnormalities. Sleep loss negatively impacts cognitive function, one untested possibility that in FXS exacerbated by abnormal sleep. We tested whether ML297, a hypnotic acting on G-protein-activated inward-rectifying potassium (GIRK) channels, could reverse phenotypes memory Fmr1−/y mice. mice exhibit reduced non-rapid eye movement (NREM) fragmented NREM architecture, altered electroencephalogram (EEG) oscillations, EEG coherence between cortical areas; these are partially reversed following ML297 administration. Treatment contextual fear or spatial learning restores consolidation During recall, show an balance of activity among hippocampal principal neurons vs. parvalbumin-expressing interneurons; this ML297. Because disruption impact neurophysiological FXS, augmenting may improve disorder.

Language: Английский

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The NKCC1 inhibitor bumetanide restores cortical feedforward inhibition and lessens sensory hypersensitivity in early postnatal fragile X mice.

Biological Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Language: Английский

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Calcium and activity-dependent signaling in the developing cerebral cortex

Development, Journal Year: 2022, Volume and Issue: 149(17)

Published: Sept. 1, 2022

Calcium influx can be stimulated by various intra- and extracellular signals to set coordinated gene expression programs into motion. As such, the precise regulation of intracellular calcium represents a nexus between environmental cues intrinsic genetic programs. Mounting evidence points role for deregulation signaling in neuropsychiatric disorders developmental origin. These findings have prompted renewed enthusiasm understanding roles during normal dysfunctional prenatal development. In this Review, we describe fundamental mechanisms through which is spatiotemporally regulated directs early neurodevelopmental events. We also discuss unanswered questions about emergence disease, provide that disruption cell-specific homeostasis and/or redeployment may contribute adult neurological disorders. propose events build nervous system will rely on gaining insights cell type-specific mechanisms. Such an enable therapeutic strategies targeting calcium-dependent mitigate disease.

Language: Английский

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What Have Organoids and Assembloids Taught Us About the Pathophysiology of Neuropsychiatric Disorders?

Biological Psychiatry, Journal Year: 2022, Volume and Issue: 93(7), P. 632 - 641

Published: Dec. 2, 2022

Language: Английский

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Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Feb. 1, 2023

Interneurons are fundamental cells for maintaining the excitation-inhibition balance in brain health and disease. While interneurons have been shown to play a key role pathophysiology of autism spectrum disorder (ASD) adult mice, little is known about how their maturation altered developing striatum ASD. Here, we aimed track striatal elucidate molecular physiological alterations Cntnap2 knockout mouse model. Using Stereo-seq single-cell RNA sequencing data, first characterized pattern expression at embryonic stages medial ganglionic eminence (MGE), transitory structure producing most cortical interneurons. We found that enriched striatum, compared cortex, particularly cholinergic then revealed enhanced MGE-derived cell proliferation, followed by increased loss during canonical window developmental death mice. uncovered specific cellular Lhx6-expressing which impacts interneuron firing properties postnatal week. Overall, our work unveils some mechanisms underlying shift trajectory greatly contribute ASD pathogenesis.

Language: Английский

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Circuit-level theories for sensory dysfunction in autism: convergence across mouse models

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

Published: Sept. 7, 2023

Individuals with autism spectrum disorder (ASD) exhibit a diverse range of behavioral features and genetic backgrounds, but whether different forms involve convergent pathophysiology brain function is unknown. Here, we analyze evidence for deficits in neural circuit across multiple transgenic mouse models ASD. We focus on sensory areas neocortex, where differences may underlie atypical processing, central feature autism. Many distinct circuit-level theories ASD have been proposed, including increased excitation–inhibition (E–I) ratio hyperexcitability, hypofunction parvalbumin (PV) interneuron circuits, impaired homeostatic plasticity, degraded coding, others. review these assess the degree convergence each. Behaviorally, our analysis reveals that innate detection behavior heightened discrimination many models. Neurophysiologically, PV E–I are prevalent only rarely generate hyperexcitability excess spiking. Instead, tuning other aspects coding commonly explain behavior. Two phenotypic clusters opposing signatures evident Such clustering could suggest physiological subtypes autism, which facilitate development tailored therapeutic approaches.

Language: Английский

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Single cell spatial biology over developmental time can decipher pediatric brain pathologies

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 199, P. 106597 - 106597

Published: July 9, 2024

Pediatric low grade brain tumors and neurodevelopmental disorders share proteins, signaling pathways, networks. They also germline mutations an impaired prenatal differentiation origin. may differ in the timing of events proliferation. We suggest that their pivotal distinct, albeit partially overlapping, outcomes relate to cell states, which depend on spatial location, gene expression during development. These attributes are crucial as develops sequentially, single-cell organization influences state, thus function. Our underlying premise is root cause pediatric differentiation. Data related tumors, disorders, (sub)types, locations, developing scant. However, emerging single technologies, including transcriptomic, biology, high-resolution imaging performed over developmental time, could be transformational deciphering pathologies thereby pharmacology.

Language: Английский

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