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GRIA1 encodes the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L-glutamate (Glu). AMPA receptors (AMPARs) are homo- or heteromeric protein complexes with four subunits, each encoded by different genes, GRIA1 to GRIA4. Although GluA1-containing AMPARs have a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. Subjects with de novo missense and nonsense GRIA1 variants were identified through international collaboration. Detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated in vitro to characterize changes in AMPAR function and expression. In addition, two Xenopus gria1 CRISPR-Cas9 F 0 models were established to characterize the in vivo consequences. Seven unrelated individuals with rare GRIA1 variants were identified. One individual carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense variations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, and p.Gly745Asp), of which the p.Ala636Thr variant was recurrent in three individuals. The cohort revealed subjects to have a recurrent neurodevelopmental disorder mostly affecting cognition and speech. Functional evaluation of major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroys the expression of GluA1-containing AMPARs. The Xenopus gria1 models show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants. These data support a developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neurodevelopmental disorders (NDDs) caused by aberrant brain growth and development are life-long, debilitating illnesses that markedly impair the quality of life. Animal models are a valuable tool for studying NDD pathobiology and therapies. Mounting evidence suggests the zebrafish (Danio rerio) as a useful model organism to study NDDs, possessing both high physiological homology to humans and sensitivity to pharmacological and genetic manipulations. Here, we summarize experimental models of NDDs in zebrafish and highlight the growing translational significance of zebrafish NDD-related phenotypes. We also emphasize the need in further development of zebrafish models of NDDs to improve our understanding of their pathogenesis and therapeutic treatments., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Abnormal repetitive behaviors (ARBs) are a prominent symptom of numerous human brain disorders and are commonly seen in rodent models as well. While rodent studies of ARBs continue to dominate the field, mounting evidence suggests that zebrafish (Danio rerio) also display ARB-like phenotypes and may therefore be a novel model organism for ARB research. In addition to clear practical research advantages as a model species, zebrafish share high genetic and physiological homology to humans and rodents, including multiple ARB-related genes and robust behaviors relevant to ARB. Here, we discuss a wide spectrum of stereotypic repetitive behaviors in zebrafish, data on their genetic and pharmacological modulation, and the overall translational relevance of fish ARBs to modeling human brain disorders. Overall, the zebrafish is rapidly emerging as a new promising model to study ARBs and their underlying mechanisms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Neurodevelopmental disorders (NDDs) are a heterogeneous group of prevalent neuropsychiatric illnesses with various degrees of social, cognitive, motor, language and affective deficits. NDDs are caused by aberrant brain development due to genetic and environmental perturbations. Common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Genetic and epigenetic/environmental factors play a key role in these NDDs with significant societal impact. Given the lack of their efficient therapies, it is important to gain further translational insights into the pathobiology of NDDs. To address these challenges, the International Stress and Behavior Society (ISBS) has established the Strategic Task Force on NDDs. Summarizing the Panel's findings, here we discuss the neurobiological mechanisms of selected common NDDs and a wider NDD+ spectrum of associated neuropsychiatric disorders with developmental trajectories. We also outline the utility of existing preclinical (animal) models for building translational and cross-diagnostic bridges to improve our understanding of various NDDs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Neurodevelopmental disorders (NDDs) are highly prevalent and severely debilitating brain illnesses caused by aberrant brain growth and development. Resulting in cognitive, social, motor, language and affective disabilities, common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Affecting neurogenesis, glia/neuronal proliferation and migration, synapse formation and myelination, aberrant neural development occurs over a substantial period of time. Genetic, epigenetic, and environmental factors play a key role in NDD pathogenesis. Animal models are an indispensable tool to study NDDs. Paralleling clinical findings, we comprehensively evaluate various preclinical tests and models which target key (social, cognitive, motor) neurobehavioral domains of ASD and other common NDDs. Covering both traditional (rodent) and alternative NDD models, we outline the emerging areas of research and emphasize how preclinical models play a key role in gaining translational and mechanistic insights into NDDs and their therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task., Areas Covered: Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies., Expert Opinion: To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or "hidden heritability," and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.