Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish DOI Creative Commons
Josiah D. Zoodsma,

Emma J. Keegan,

Gabrielle Moody

и другие.

Molecular Autism, Год журнала: 2022, Номер 13(1)

Опубликована: Сен. 22, 2022

Abstract Background Autism spectrum disorder (ASD), like many neurodevelopmental disorders, has complex and varied etiologies. Advances in genome sequencing have identified multiple candidate genes associated with ASD, including dozens of missense nonsense mutations the NMDAR subunit GluN2B, encoded by GRIN2B . NMDARs are glutamate-gated ion channels key synaptic functions excitatory neurotransmission. How alterations these proteins impact neurodevelopment is poorly understood, part because knockouts GluN2B rodents lethal. Methods Here, we use CRISPR-Cas9 to generate zebrafish lacking ( grin2B −/− ). Using fish, run an array behavioral tests perform whole-brain larval imaging assay developmental roles GluN2B. Results We demonstrate that displays similar structural functional properties human Zebrafish ) surprisingly survive into adulthood. Given prevalence social deficits assayed preference fish. Wild-type fish develop a strong 3 weeks post fertilization. In contrast, at this age exhibit significantly reduced preference. Notably, lack does not result broad disruption neurodevelopment, as larvae do show spontaneous or photic-evoked movements, capable prey capture, learning. Whole-brain revealed reduction inhibitory neuron marker subpallium, region linked ASD humans, but showed overall brain size E / I balance comparable wild type. Limitations while useful studying unlikely model nuanced complete loss function. Additionally, detailed mammalian homologies for subdivisions fully resolved. Conclusions completely NMDAR, unlike rodent models, viable they highly specific deficit behavior. As such, affords unique opportunity study etiologies establish disease-relevant vivo future studies.

Язык: Английский

Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment DOI Creative Commons
Xiang-Ling Meng,

David Yao,

Kent Imaizumi

и другие.

Nature, Год журнала: 2023, Номер 622(7982), С. 359 - 366

Опубликована: Сен. 27, 2023

Abstract The assembly of cortical circuits involves the generation and migration interneurons from ventral to dorsal forebrain 1–3 , which has been challenging study at inaccessible stages late gestation early postnatal human development 4 . Autism spectrum disorder other neurodevelopmental disorders (NDDs) have associated with abnormal interneuron 5 but these NDD genes affect migration, how they mediate effects remains unknown. We previously developed a platform in subpallial organoids assembloids 6 Here we integrate CRISPR screening investigate involvement 425 development. first screen aimed revealed 13 candidate genes, including CSDE1 SMAD4 subsequently conducted an more than 1,000 that identified 33 cytoskeleton-related endoplasmic reticulum-related gene LNPK discovered that, during reticulum is displaced along leading neuronal branch before nuclear translocation. deletion interfered this displacement resulted migration. These results highlight power CRISPR-assembloid systematically map onto reveal disease mechanisms.

Язык: Английский

Процитировано

74
Somatostatin interneurons control the timing of developmental desynchronization in cortical networks DOI Creative Commons
Laura Mòdol, Monika Moissidis, Martijn Selten

и другие.

Neuron, Год журнала: 2024, Номер 112(12), С. 2015 - 2030.e5

Опубликована: Апрель 9, 2024

Synchronous neuronal activity is a hallmark of the developing brain. In mouse cerebral cortex, decorrelates during second week postnatal development, progressively acquiring characteristic sparse pattern underlying integration sensory information. The maturation inhibition seems critical for this process, but interneurons involved in crucial transition network cortex remain unknown. Using vivo longitudinal two-photon calcium imaging period that precedes change from highly synchronous to decorrelated activity, we identify somatostatin-expressing (SST+) as modulators switch mice. Modulation SST+ cells accelerates or delays decorrelation cortical process involves regulating parvalbumin-expressing (PV+) interneurons. critically link inputs with local circuits, controlling neural dynamics while modulating other into nascent circuits.

Язык: Английский

Процитировано

21
The role of the prefrontal cortex in social interactions of animal models and the implications for autism spectrum disorder DOI Creative Commons
Alok Nath Mohapatra, Shlomo Wagner

Frontiers in Psychiatry, Год журнала: 2023, Номер 14

Опубликована: Июнь 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.

Язык: Английский

Процитировано

32
Improvement of sensory deficits in fragile X mice by increasing cortical interneuron activity after the critical period DOI Creative Commons
Nazim Kourdougli, Anand Suresh, Benjamin Liu

и другие.

Neuron, Год журнала: 2023, Номер 111(18), С. 2863 - 2880.e6

Опубликована: Июль 13, 2023

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to pathophysiology neurodevelopmental disorders. Using all-optical vivo approaches, we find that parvalbumin (PV) INs and their immature precursors are hypoactive transiently decoupled from excitatory neurons postnatal mouse somatosensory cortex (S1) Fmr1 KO mice, a model fragile X syndrome (FXS). This leads loss (PV-INs) both mice humans with FXS. Increasing activity future PV-INs neonatal restores PV-IN density ameliorates transcriptional dysregulation S1, but not circuit dysfunction. Critically, administering an allosteric modulator Kv3.1 channels after S1 critical period does rescue dynamics tactile defensiveness. Symptoms FXS related disorders be mitigated by targeting PV-INs.

Язык: Английский

Процитировано

32
VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome DOI Creative Commons
Kevin M. Goff, Sophie R Liebergall,

Evan Jiang

и другие.

Cell Reports, Год журнала: 2023, Номер 42(6), С. 112628 - 112628

Опубликована: Июнь 1, 2023

Dravet syndrome (DS) is a severe neurodevelopmental disorder caused by loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1. We recently showed that neocortical vasoactive intestinal peptide interneurons (VIP-INs) express Nav1.1 and are hypoexcitable DS (Scn1a+/−) mice. Here, we investigate VIP-IN function at circuit behavioral level performing vivo 2-photon calcium imaging awake wild-type (WT) Scn1a+/− pyramidal neuron activation during transition from quiet wakefulness to active running diminished mice, optogenetic of VIP-INs restores activity WT levels locomotion. selective Scn1a deletion reproduces core autism-spectrum-disorder-related behaviors addition cellular- circuit-level deficits function, but without epilepsy, sudden death, or avoidance seen global model. Hence, impaired vivo, may underlie non-seizure cognitive comorbidities DS.

Язык: Английский

Процитировано

25
Network state transitions during cortical development DOI
M. Wu, Nazim Kourdougli, Carlos Portera‐Cailliau

и другие.

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(8), С. 535 - 552

Опубликована: Май 23, 2024

Язык: Английский

Процитировано

16
Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior DOI
Jerika J. Barron, Nicholas M. Mroz, Sunrae E. Taloma

и другие.

Science, Год журнала: 2024, Номер 386(6721)

Опубликована: Окт. 31, 2024

The innate immune system shapes brain development and is implicated in neurodevelopmental diseases. It critical to define the relevant cells signals their impact on circuits. In this work, we found that group 2 lymphoid (ILC2s) cytokine interleukin-13 (IL-13) signaled directly inhibitory interneurons increase synapse density developing mouse brain. ILC2s expanded produced IL-13 meninges. Loss of or signaling decreased inhibitory, but not excitatory, cortical synapses. Conversely, were sufficient pathway led selective impairments social interaction. These data a type neuroimmune circuit early life behavior.

Язык: Английский

Процитировано

13
PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors DOI
Tyrone DeSpenza,

Emre Kiziltug,

Garrett Allington

и другие.

Nature Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Язык: Английский

Процитировано

2
A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome DOI Creative Commons
Ania Fiksinski, Gil D. Hoftman, Jacob Vorstman

и другие.

Molecular Psychiatry, Год журнала: 2022, Номер 28(1), С. 341 - 353

Опубликована: Окт. 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.

Язык: Английский

Процитировано

38
Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders DOI
David Exposito-Alonso, Beatriz Rico

Annual Review of Genetics, Год журнала: 2022, Номер 56(1), С. 391 - 422

Опубликована: Сен. 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.

Язык: Английский

Процитировано

31