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AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+ -impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca 2+ transport and AMPAR currents.”

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease. Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

In a randomized, controlled trial involving infants with extremely low birth weight, parenteral amino acids at a dose of 1 g per day for 5 days after birth did not increase neurodisability-free survival at 2 years.

In this multicenter, randomized trial involving extremely preterm infants, high-dose erythropoietin administered from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age.

Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene–environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic ‘priming’ of offspring microglia and postnatal immune–brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.The maternal immune activation (MIA) hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment. This Review examines the emerging human evidence for an association between MIA and childhood neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome.

Less invasive surfactant administration (LISA) is a method to deliver surfactant to spontaneously breathing premature infants via a thin catheter. Here we report the two-year outcome from the AMV (avoid mechanical ventilation) study, the first randomized controlled trial on this mode of surfactant delivery. No statistically significant differences in weight, length or neurodevelopmental outcome (Bayley II scores) were found between the LISA intervention group (n = 95) and the control group (n = 84) that received standard treatment.Conclusion: No differences in outcome were observed at 2 years. LISA seems safe in that aspect.What is Known:• LISA is a method that is in increasing use for surfactant delivery to spontaneously breathing infants. LISA reduces the need for mechanical ventilation.What is New:• Outcome data at 2 years from the first randomized study with LISA raise no safety concerns in comparison to a group of infants that received standard treatment.

Atypical brain connectivity is a major contributor to the pathophysiology of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASDs). TAOK2 is one of several genes in the 16p11.2 microdeletion region, but whether it contributes to NDDs is unknown. We performed behavioral analysis on Taok2 heterozygous (Het) and knockout (KO) mice and found gene dosage-dependent impairments in cognition, anxiety, and social interaction. Taok2 Het and KO mice also have dosage-dependent abnormalities in brain size and neural connectivity in multiple regions, deficits in cortical layering, dendrite and synapse formation, and reduced excitatory neurotransmission. Whole-genome and -exome sequencing of ASD families identified three de novo mutations in TAOK2 and functional analysis in mice and human cells revealed that all the mutations impair protein stability, but they differentially impact kinase activity, dendrite growth, and spine/synapse development. Mechanistically, loss of Taok2 activity causes a reduction in RhoA activation, and pharmacological enhancement of RhoA activity rescues synaptic phenotypes. Together, these data provide evidence that TAOK2 is a neurodevelopmental disorder risk gene and identify RhoA signaling as a mediator of TAOK2-dependent synaptic development.

Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data. How neurodevelopmental disorder-associated risk genes are translated into spatially patterned brain vulnerabilities is unclear. Here, the authors show that disorder-specific patterns of neuroanatomical changes are aligned to brain expression maps of disease risk genes in healthy subjects.

The mental health of youth with chronic kidney disease (CKD) has been increasingly recognized as an area of clinical need. The development of mental health concerns is influenced by a range of physiological, psychological, and environmental factors. Some of these factors are common across child development, but some are more unique to youth with CKD. Mental health concerns are associated with increased risk for a range of poor medical outcomes (e.g., adherence, risk of transplant rejection) and quality of life concerns. In this educational review, we discuss the current evidence base regarding the development of mental health concerns in youth with CKD. The review covers multiple domains including mood and anxiety disorders, traumatic stress, and neurodevelopmental disorders. Estimated prevalence and hypothesized risk factors are outlined, and the potential impact of mental health on medical care and functional outcomes are reviewed. Finally, we introduce options for intervention to support positive mental health and offer recommendations for building access to mental health care and improving the mental health education/training of medical professionals. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Sleep is essential for brain development and overall health, particularly in children with neurodevelopmental disorders (NDDs). Sleep disruptions can considerably impact brain structure and function, leading to dysfunction of neurotransmitter systems, metabolism, hormonal balance and inflammatory processes, potentially contributing to the pathophysiology of NDDs. This Review examines the prevalence, types and mechanisms of sleep disturbances in children with NDDs, including autism spectrum disorder, attention-deficit hyperactivity disorder and various genetic syndromes. Common sleep disorders in these populations include insomnia, hypersomnia, circadian rhythm disorders, sleep-related breathing disorders and parasomnias, with underlying factors often involving genetic, neurobiological, environmental and neurophysiological influences. Sleep problems such as insomnia, night awakenings and sleep fragmentation are closely linked to both internalizing symptoms such as anxiety and depression, and externalizing behaviours such as hyperactivity and aggression. Assessment of sleep in children with NDDs presents unique challenges owing to communication difficulties, comorbid conditions and altered sensory processing. The Review underscores the importance of further research to unravel the complex interactions between sleep and neurodevelopment, advocating for longitudinal studies and the identification of predictive biomarkers. Understanding and addressing sleep disturbances in NDDs is crucial for improving developmental outcomes and the overall quality of life for affected individuals and their families. In this Review, the authors provide a comprehensive overview of the prevalence and impact of various sleep disturbances in children with neurodevelopmental disorders. The authors discuss potential underlying mechanisms of sleep disorders in this population, with clues from genetic disorders, and highlight the complex bidirectional relationship between sleep and neurodevelopment. Key points Sleep is essential for several neurodevelopmental processes, such as synaptic plasticity, neural reorganization and cognitive and emotional processes. An impairment of sleep mechanisms can indicate important developmental consequences for both children with typical or atypical neurodevelopment. The pathophysiology of sleep disorders in children with a neurodevelopmental disorder (NDD) is linked to genetic and epigenetic factors that influence endogenous dysfunction in the release of hormones, neurotransmitters and perception of zeitgeber. Understanding the complex relationship between sleep patterns and NDDs is essential for developing targeted interventions and enhancing the overall quality of life for affected individuals and their families. Future research involving longitudinal studies to track sleep patterns and neurodevelopmental outcomes is needed to further elucidate the complex interactions between sleep and NDDs and understand the long-term effects of sleep disturbances and interventions.