UNASSIGNED: Human cerebral organoids (hCOs) derived from pluripotent stem cells are very promising for the study of neurodevelopment and the investigation of the healthy or diseased brain. To help establish hCOs as a powerful research model, it is essential to perform the morphological characterization of their cellular components in depth.
UNASSIGNED: In this study, we analyzed the cell types consisting of hCOs after culturing for 45 days using immunofluorescence and reverse transcriptase qualitative polymerase chain reaction (RT-qPCR) assays. We also analyzed their subcellular morphological characteristics by transmission electron microscopy (TEM).
UNASSIGNED: Our results show the development of proliferative zones to be remarkably similar to those found in human brain development with cells having a polarized structure surrounding a central cavity with tight junctions and cilia. In addition, we describe the presence of immature and mature migrating neurons, astrocytes, oligodendrocyte precursor cells, and microglia-like cells.
UNASSIGNED: The ultrastructural characterization presented in this study provides valuable information on the structural development and morphology of the hCO, and this information is of general interest for future research on the mechanisms that alter the cell structure or function of hCOs.

Proprioception has long been linked with emotional dysregulation in neurotypical adults. Neuropediatric disorders such as autism spectrum disorder (ASD) and cerebral palsy (CP) are distinct entities and yet both present with deficits and challenges in sensory processing and the regulation of emotions. This study aimed to explore the relationship between proprioception and emotional-social performance in children and to compare proprioception and emotional-social performance in different underlying neurodevelopmental conditions. For this purpose, this cross-sectional study included 42 children with ASD, 34 children with CP and 50 typically developing peers. Proprioceptive acuity, proprioceptive reactive behavior as well as emotion regulation and social responsiveness were assessed. The results show a significant correlation between proprioceptive deficits and emotional difficulties in this pediatric sample, with distinct proprioceptive impairment patterns according to the underlying neurological disorder. Children with CP showed significant emotional knowledge deficits, while children with ASD predominantly showed challenges in social responsiveness. These data thus suggest a differentiated impact of proprioception on emotional-social performance in neurodevelopmental disorders and highlight proprioception as a potential therapeutic target for balancing emotion regulation in children with neurodevelopmental conditions.

Neurodevelopmental disorders can be studied from two distinct perspectives: an internal approach, which examines the causes and consequences of these disorders; and a contextual approach, which considers the role of the family in the lives of children and adolescents. Research has demonstrated that the most significant form of family involvement in families raising a child with NDD is through homework. This involvement has been shown to have an emotional impact on children with neurodevelopmental disorders such as ADHD or dyslexia. The objective of this study is to review published articles on homework and neurodevelopmental disorders, with particular attention to the role of the family and the emotional health of children and families.
METHODS: The review followed the PRISMA guidelines. The final sample consisted of 11 articles, with samples ranging from less than 30 participants to more than 100 at the international level.
RESULTS: The results demonstrate the complex methodological and bibliometric picture of the final sample, as well as the many emotional and contextual variables that influence the relationship between homework and neurodevelopmental disorders.
CONCLUSIONS: Future research should consider how emotional health affects the engagement of families with children with neurodevelopmental disorders.

The endocannabinoid system has been linked to various physiological and pathological processes, because it plays a neuromodulator role in the central nervous system. In this sense, cannabinoids have been used off-label for neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHA), as well as in Alzheimer\'s disease (AD), a more prevalent neurodegenerative disease. Thus, this study aims, through a comprehensive literature review, to arrive at a better understanding of the impact of cannabinoids in the therapeutic treatment of patients with ASD, ADHD, and Alzheimer\'s disease (AD). Overall, cannabis products rich in CBD displayed a higher therapeutic potential for ASD children, while cannabis products rich in THC have been tested more for AD therapy. For ADHD, the clinical studies are incipient and inconclusive, but promising. In general, the main limitations of the clinical studies are the lack of standardization of the cannabis-based products consumed by the participants, a lack of scientific rigor, and the small number of participants.

Ageing is a continuous process that can cause neurodevelopmental changes in the body. Several studies have examined its effects, but few have focused on how time affects biological processes in the early stages of brain development. As studying the changes that occur in the early stages of life is important to prevent age-related neurological and psychiatric disorders, we aim to focus on these changes. The transcriptomic markers of ageing that are common to the analysed brain regions of C57Bl/6J mice were identified after conducting two-way ANOVA tests and effect size analysis on the time courses of gene expression profiles in various mouse brain regions. A total of 16,374 genes (59.9%) significantly changed their expression level, among which 7600 (27.8%) demonstrated tissue-dependent differences only, and 1823 (6.7%) displayed time-dependent and tissue-independent responses. Focusing on genes with at least a large effect size gives the list of potential biomarkers 12,332 (45.1%) and 1670 (6.1%) genes, respectively. There were 305 genes that exhibited similar significant time response trends (independently of the brain region). Samples from an 11-day-old mouse embryo validated the identified early-stage brain ageing markers. The overall functional analysis revealed tRNA and rRNA processing in the mitochondrion and contact activation system (CAS), as well as the kallikrein/kinin system (KKS), together with clotting cascade and defective factor F9 activation being affected by ageing. Most ageing-related pathways were significantly enriched, especially those that are strongly connected to development processes and neurodegenerative diseases.

Glutamate is the main excitatory neurotransmitter in the brain wherein it controls cognitive functional domains and mood. Indeed, brain areas involved in memory formation and consolidation as well as in fear and emotional processing, such as the hippocampus, prefrontal cortex, and amygdala, are predominantly glutamatergic. To ensure the physiological activity of the brain, glutamatergic transmission is finely tuned at synaptic sites. Disruption of the mechanisms responsible for glutamate homeostasis may result in the accumulation of excessive glutamate levels, which in turn leads to increased calcium levels, mitochondrial abnormalities, oxidative stress, and eventually cell atrophy and death. This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism in several diseases of the central nervous system, including neurodevelopmental, substance abuse, and psychiatric disorders. On the other hand, these disorders share neuroplasticity impairments in glutamatergic brain areas, which are accompanied by structural remodeling of glutamatergic neurons. In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders. Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions. Although clinical evidence is still limited and more studies are required, the regulation of glutamate homeostasis is attracting attention as a potential crucial target for the control of brain diseases.

BACKGROUND: Parents of children with a neurodevelopmental disorder (NDD) experience more stress than parents of typically developing children. In a cocreation process with experts and parents, a low-threshold application that uses exercises based on the principles of positive psychology and mindfulness was developed. This application, called \"Adappt,\" aims at enhancing the ability to adapt of the parents and caregivers of children with NDDs and at supporting their mental health. This protocol describes the evaluation study of the effectiveness of Adappt, its core working mechanisms and user experiences.
METHODS: A pragmatic international multicenter randomized controlled trial will compare the effectiveness of Adappt with a (delayed) waitlist control condition. At least 212 parents or primary caregivers of children younger than 18 years diagnosed with or suspected of a NDD will be randomly assigned to the intervention or waitlist control condition. Participants are excluded if they have severe anxiety or depression levels or are in treatment for mental health issues. Measures will be collected online at baseline, post-intervention (1 month after baseline), and 4 and 7 months after baseline. The primary outcome is the improvement in generic sense of ability to adapt as measured with the Generic Sense of Ability to Adapt Scale (GSAAS; (Front Psychol 14:985408, 2023)) at 4-month follow-up. Secondary outcomes are mental well-being, (parental) distress, and client satisfaction with \"Adappt.\"
CONCLUSIONS: Results of this study will contribute to knowledge on the effectiveness of a low-threshold application for parents of children with a NDD in multiple countries. If the application is found to be effective in improving mental health, recommendations will be made for implementation in health care.
BACKGROUND: This study is registered on clinicaltrials.gov (NCT06248762) on February 8, 2024, and the Open Science Framework ( https://osf.io/5znqv ).

Heterozygous de novo mutations in the Activity-Dependent Neuroprotective Homeobox (ADNP) gene underlie Helsmoortel-Van der Aa syndrome (HVDAS). Most of these mutations are situated in the last exon and we previously demonstrated escape from nonsense-mediated decay by detecting mutant ADNP mRNA in patient blood. In this study, wild-type and ADNP mutants are investigated at the protein level and therefore optimal detection of the protein is required. Detection of ADNP by means of western blotting has been ambiguous with reported antibodies resulting in non-specific bands without unique ADNP signal. Validation of an N-terminal ADNP antibody (Aviva Systems) using a blocking peptide competition assay allowed to differentiate between specific and non-specific signals in different sample materials, resulting in a unique band signal around 150 kDa for ADNP, above its theoretical molecular weight of 124 kDa. Detection with different C-terminal antibodies confirmed the signals at an observed molecular weight of 150 kDa. Our antibody panel was subsequently tested by immunoblotting, comparing parental and homozygous CRISPR/Cas9 endonuclease-mediated Adnp knockout cell lines and showed disappearance of the 150 kDa signal, indicative for intact ADNP. By means of both a GFPSpark and Flag-tag N-terminally fused to a human ADNP expression vector, we detected wild-type ADNP together with mutant forms after introduction of patient mutations in E. coli expression systems by site-directed mutagenesis. Furthermore, we were also able to visualize endogenous ADNP with our C-terminal antibody panel in heterozygous cell lines carrying ADNP patient mutations, while the truncated ADNP mutants could only be detected with epitope-tag-specific antibodies, suggesting that addition of an epitope-tag possibly helps stabilizing the protein. However, western blotting of patient-derived hiPSCs, immortalized lymphoblastoid cell lines and post-mortem patient brain material failed to detect a native mutant ADNP protein. In addition, an N-terminal immunoprecipitation-competent ADNP antibody enriched truncating mutants in overexpression lysates, whereas implementation of the same method failed to enrich a possible native mutant protein in immortalized patient-derived lymphoblastoid cell lines. This study aims to shape awareness for critical assessment of mutant ADNP protein analysis in Helsmoortel-Van der Aa syndrome.

OBJECTIVE: An update on the plasticity of the brain networks involved in autism (autism spectrum disorders [ASD]), and the increasing role of their synapses and primary non-motile cilia.
METHODS: Data from PubMed and Google on this subject, published until February 2024, were analyzed.
RESULTS: Structural and functional brain characteristics and genetic particularities involving synapses and cilia that modify neuronal circuits are observed in ASD, such as reduced pruning of dendrites, minicolumnar pathology, or persistence of connections usually doomed to disappear. Proteins involved in synapse functions (such as neuroligins and neurexins), in the postsynaptic architectural scaffolding (such as Shank proteins) or in cilia functions (such as IFT-independent kinesins) are often abnormal. There is an increase in glutaminergic transmission and a decrease in GABA inhibition. ASD may occur in genetic ciliopathies. The means of modulating these specificities, when deemed useful, are described.
CONCLUSIONS: The wide range of clinical manifestations of ASD is strongly associated with abnormalities in the morphology, functions, and plasticity of brain networks, involving their synapses and non-motile cilia. Their modulation offers important research perspectives on treatments when needed, especially since brain plasticity persists much later than previously thought. Improved early detection of ASD and additional studies on synapses and primary cilia are needed.

Influenza A virus (IAV) infection during pregnancy can increase the risk for neurodevelopmental disorders in the offspring, however, the underlying neurobiological mechanisms are largely unknown. To recapitulate viral infection, preclinical studies have traditionally focused on using synthetic viral mimetics, rather than live IAV, to examine consequences of maternal immune activation (MIA)-dependent processes on offspring. In contrast, few studies have used live IAV to assess effects on global gene expression, and none to date have addressed whether moderate IAV, mimicking seasonal influenza disease, alters normal gene expression trajectories in different brain regions across different stages of development. Herein, we show that moderate IAV infection during pregnancy, which causes mild maternal disease and no overt foetal complications in utero, induces lasting effects on the offspring into adulthood. We observed behavioural changes in adult offspring, including disrupted pre-pulse inhibition, dopaminergic hyper-responsiveness, and spatial recognition memory deficits. Gene profiling in the offspring brain from neonate to adolescence revealed persistent alterations to normal gene expression trajectories in the hippocampus, cerebellum, prefrontal cortex, and hypothalamus. Alterations were found in genes involved in inflammation and neurogenesis, which were predominately dysregulated in neonatal and early adolescent offspring. Notably, late adolescent offspring born from IAV infected mice displayed altered microglial morphology in the hippocampus. In conclusion, we show that moderate IAV during pregnancy perturbs neurodevelopmental trajectories in the offspring, including alterations in the neuroinflammatory gene expression profiled and microglial number and morphology in the hippocampus, resulting in behavioural changes in adult offspring. Such early perturbations may underlie the vulnerability in human offspring for the later development of neurodevelopmental disorders, including schizophrenia. Our work highlights the importance of using live IAV in developing novel preclinical models that better recapitulate the real-world impact of inflammatory insults during pregnancy on the offspring neurodevelopmental trajectory and disease susceptibility later in life.