Novel roles for immune molecules in neural development: implications for neurodevelopmental disorders

Transtornos do desenvolvimento neural constituem um grupo bastante diverso de problemas identificáveis clinicamente, que decorrem de perturbações do desenvolvimento neurológico, manifestam-se desde a infância, mesmo que sejam reconhecidos somente mais tarde, são persistentes, geram algum grau de limitação seja na capacidade de aprendizagem, na comunicação, ou na interação social, o que produz reflexos na vida escolar, laboral ou outras áreas da vida. Os principais transtornos do desenvolvimento neural são o transtorno do espectro autista (autismo), a deficiência intelectual (retardo mental ou deficiência mental), o transtorno do déficit de atenção e hiperatividade (TDAH), a epilepsia dos transtornos do desenvolvimento, a dislexia do desenvolvimento, a discalculia do desenvolvimento, a gagueira do desenvolvimento e a paralisia cerebral. Os transtornos do desenvolvimento neural podem ter diversas causas, genéticas e não genéticas (ambientais), e muitas vezes ambas contribuem para a ocorrência do transtorno. O objetivo deste trabalho é compreender os mecanismos envolvidos na origem dos transtornos de desenvolvimento neural durante a formação cerebral a partir de trabalhos da base de dados do índice Medline. Neurodevelopmental disorders are a very diverse group of clinically identifiable disorders that result from derangement of neural development, they are persistent and manifest from childhood, even if they are only recognized later, and generate some degree of limitation in the learning capacity, communication, or social interaction, which produces reflexes in school, work or other areas of life. The main neurodevelopmental disorders are autism spectrum disorder (autism), intellectual disability (mental retardation or mental disability), attention deficit hyperactivity disorder (ADHD), developmental epilepsy, developmental dyslexia, developmental dyscalculia, developmental stuttering and cerebral palsy. Neurodevelopmental disorders may have several causes, genetic and non-genetic (environmental), and often both act simultaneously. The aim of this work is to understand the mechanisms involved in the origin of neural development disorders during brain formation based on words from the Medline index database.

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Unraveling Molecular Pathways Altered in MeCP2-Related Syndromes, in the Search for New Potential Avenues for Therapy

Biomedicines ◽

10.3390/biomedicines9020148 ◽

2021 ◽

Vol 9 (2) ◽

pp. 148

Author(s):

Alba-Aina Castells ◽

Rafel Balada ◽

Alba Tristán-Noguero ◽

Mar O’Callaghan ◽

Elisenda Cortès-Saladelafont ◽

...

Keyword(s):

Disease Progression ◽

Rett Syndrome ◽

Neural Development ◽

Neurodevelopmental Disorders ◽

Clinical Symptoms ◽

Interleukin 1 ◽

Loss Of Function ◽

Potential Biomarker ◽

Mecp2 Duplication Syndrome ◽

Duplication Syndrome

Methyl-CpG-binding protein 2 (MeCP2) is an X-linked epigenetic modulator whose dosage is critical for neural development and function. Loss-of-function mutations in MECP2 cause Rett Syndrome (RTT, OMIM #312750) while duplications in the Xq28 locus containing MECP2 and Interleukin-1 receptor-associated kinase 1 (IRAK1) cause MECP2 duplication syndrome (MDS, OMIM #300260). Both are rare neurodevelopmental disorders that share clinical symptoms, including intellectual disability, loss of speech, hand stereotypies, vasomotor deficits and seizures. The main objective of this exploratory study is to identify novel signaling pathways and potential quantitative biomarkers that could aid early diagnosis and/or the monitoring of disease progression in clinical trials. We analyzed by RT-PCR gene expression in whole blood and microRNA (miRNA) expression in plasma, in a cohort of 20 females with Rett syndrome, 2 males with MECP2 duplication syndrome and 28 healthy controls, and correlated RNA expression with disease and clinical parameters. We have identified a set of potential biomarker panels for RTT diagnostic and disease stratification of patients with microcephaly and vasomotor deficits. Our study sets the basis for larger studies leading to the identification of specific miRNA signatures for early RTT detection, stratification, disease progression and segregation from other neurodevelopmental disorders. Nevertheless, these data will require verification and validation in further studies with larger sample size including a whole range of ages.

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Spatiotemporal dynamics of human microglia are linked with brain developmental processes across the lifespan

10.1101/2021.08.07.455365 ◽

2021 ◽

Author(s):

David A. Menassa ◽

Tim A. O. Muntslag ◽

Maria Martin-Estebane ◽

Liam Barry-Carroll ◽

Mark A. Chapman ◽

...

Keyword(s):

Neural Development ◽

Neurodevelopmental Disorders ◽

Spatiotemporal Dynamics ◽

Post Mortem ◽

Human Microglia ◽

Human Lifespan ◽

Proliferation And Apoptosis ◽

Solid Foundation ◽

Microglial Development ◽

Human Telencephalon

Microglia, the brain's resident macrophages, shape neural development and wiring, and are key neuroimmune hubs in the pathological signature of neurodevelopmental disorders. In the human brain, microglial development has not been carefully examined yet, and most of our knowledge derives from rodents. We established an unprecedented collection of 97 post-mortem tissues enabling quantitative, sex-matched, detailed analysis of microglia across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing novel waves in microglial density across gestation and infancy, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNAseq and single-cell RNAseq datasets. This study provides unparalleled insight and detail into the spatiotemporal dynamics of microglia across the human lifespan. Our findings serve as a solid foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

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Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish

10.1101/2021.06.30.450513 ◽

2021 ◽

Author(s):

Ester Anton-Galindo ◽

Elisa Dalla Vecchia ◽

Javier G Orlandi ◽

Gustavo Castro ◽

Emilio Gualda ◽

...

Keyword(s):

Neural Development ◽

Neurodevelopmental Disorders ◽

Genome Engineering ◽

Developmental Stages ◽

Brain Activity ◽

Autism Spectrum ◽

Wild Type ◽

Zebrafish Model ◽

Risk Variants

Genetic risk variants in YWHAZ, encoding 14-3-ζ, have been found to contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we have used a zebrafish model to further understand the mechanisms by which YWHAZ contribute to neurodevelopmental disorders. We first observed pan-neuronal expression of ywhaz during developmental stages, suggesting an important role of this gene in neural development. During adulthood ywhaz expression was restricted to Purkinje cells in the cerebellum, a region that shows alterations in autistic patients. We then established a novel stable ywhaz knockout (KO) zebrafish line using CRISPR/Cas9 genome engineering. We performed whole-brain calcium imaging in wild-type (WT) and ywhaz KO larvae and found altered neural activity and functional connectivity in the hindbrain. Interestingly, adult ywhaz KO fish also display decreased levels of dopamine and serotonin in the hindbrain and freeze when exposed to novel stimuli, a phenotype that can be reversed with fluoxetine and quinpirole, drugs that target serotonin and dopamine neurotransmission. Together, these findings suggest an important role for ywhaz in establishing neuronal connectivity during developmental stages. ywhaz deficiency leads to impaired dopamine and serotonin neurotransmission that may underlie the altered behaviour observed during adulthood.

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Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders

Biochemical Society Transactions ◽

10.1042/bst20150168 ◽

2015 ◽

Vol 43 (6) ◽

pp. 1259-1265 ◽

Cited By ~ 4

Author(s):

Francesca Sartor ◽

Jihan Anderson ◽

Colin McCaig ◽

Zosia Miedzybrodzka ◽

Berndt Müller

Keyword(s):

Neural Development ◽

Neurodevelopmental Disorders ◽

Nuclear Export ◽

Mrna Splicing ◽

Mrna Metabolism ◽

Aberrant Gene Expression ◽

Genes Encoding ◽

And Function ◽

Aberrant Gene ◽

New Strategies

Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention.

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Endocrine Insights into the Pathophysiology of Autism Spectrum Disorder

The Neuroscientist ◽

10.1177/1073858420952046 ◽

2020 ◽

pp. 107385842095204

Author(s):

Hayley A. Wilson ◽

Carolyn Creighton ◽

Helen Scharfman ◽

Elena Choleris ◽

Neil J. MacLusky

Keyword(s):

Risk Factors ◽

Autism Spectrum Disorder ◽

Neural Development ◽

Neurodevelopmental Disorders ◽

Early Life ◽

Normal Development ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Glucocorticoid Hormones ◽

The Brain

Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders that affects males more frequently than females. Numerous genetic and environmental risk factors have been suggested to contribute to the development of ASD. However, no one factor can adequately explain either the frequency of the disorder or the male bias in its prevalence. Gonadal, thyroid, and glucocorticoid hormones all contribute to normal development of the brain, hence perturbations in either their patterns of secretion or their actions may constitute risk factors for ASD. Environmental factors may contribute to ASD etiology by influencing the development of neuroendocrine and neuroimmune systems during early life. Emerging evidence suggests that the placenta may be particularly important as a mediator of the actions of environmental and endocrine risk factors on the developing brain, with the male being particularly sensitive to these effects. Understanding how various risk factors integrate to influence neural development may facilitate a clearer understanding of the etiology of ASD.

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Cannabidiol and Neurodevelopmental Disorders in Children

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.643442 ◽

2021 ◽

Vol 12 ◽

Author(s):

Keith A. Kwan Cheung ◽

Murray D. Mitchell ◽

Helen S. Heussler

Keyword(s):

Neural Development ◽

Neurodevelopmental Disorders ◽

Endocannabinoid System ◽

Autism Spectrum ◽

Mechanisms Of Action ◽

Signalling Pathways ◽

Therapeutic Effects ◽

Improve Quality ◽

Medicinal Cannabis

Neurodevelopmental and neuropsychiatric disorders (such as autism spectrum disorder) have broad health implications for children, with no definitive cure for the vast majority of them. However, recently medicinal cannabis has been successfully trialled as a treatment to manage many of the patients' symptoms and improve quality of life. The cannabinoid cannabidiol, in particular, has been reported to be safe and well-tolerated with a plethora of anticonvulsant, anxiolytic and anti-inflammatory properties. Lately, the current consensus is that the endocannabinoid system is a crucial factor in neural development and health; research has found evidence that there are a multitude of signalling pathways involving neurotransmitters and the endocannabinoid system by which cannabinoids could potentially exert their therapeutic effects. A better understanding of the cannabinoids' mechanisms of action should lead to improved treatments for neurodevelopmental disorders.

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Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What’s behind Neuro-RACopathies

Cells ◽

10.3390/cells10123395 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3395

Author(s):

Marcello Scala ◽

Masashi Nishikawa ◽

Koh-ichi Nagata ◽

Pasquale Striano

Keyword(s):

Neural Development ◽

Neurodevelopmental Disorders ◽

Rho Gtpases ◽

Cell Cycle Progression ◽

Current Knowledge ◽

Proper Function ◽

Neurological Involvement ◽

Nucleotide Exchange ◽

Homologous Proteins ◽

Pathophysiological Mechanisms

Rho family guanosine triphosphatases (GTPases) regulate cellular signaling and cytoskeletal dynamics, playing a pivotal role in cell adhesion, migration, and cell cycle progression. The Rac subfamily of Rho GTPases consists of three highly homologous proteins, Rac 1–3. The proper function of Rac1 and Rac3, and their correct interaction with guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) are crucial for neural development. Pathogenic variants affecting these delicate biological processes are implicated in different medical conditions in humans, primarily neurodevelopmental disorders (NDDs). In addition to a direct deleterious effect produced by genetic variants in the RAC genes, a dysregulated GTPase activity resulting from an abnormal function of GEFs and GAPs has been involved in the pathogenesis of distinctive emerging conditions. In this study, we reviewed the current pertinent literature on Rac-related disorders with a primary neurological involvement, providing an overview of the current knowledge on the pathophysiological mechanisms involved in the neuro-RACopathies.

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Nanoplasmonic immunosensor for the detection of SCG2, a candidate serum biomarker for the early diagnosis of neurodevelopmental disorder

Scientific Reports ◽

10.1038/s41598-021-02262-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

So-Hee Lim ◽

Yun-Ju Sung ◽

Narae Jo ◽

Na-Yoon Lee ◽

Kyoung-Shim Kim ◽

...

Keyword(s):

Early Diagnosis ◽

Neural Development ◽

Neurodevelopmental Disorders ◽

Hippocampal Neurons ◽

Pediatric Patients ◽

Neurodevelopmental Disorder ◽

Diagnostic Methods ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Highly Sensitive

AbstractThe neural circuits of the infant brain are rapidly established near 6 months of age, but neurodevelopmental disorders can be diagnosed only at the age of 2–3 years using existing diagnostic methods. Early diagnosis is very important to alleviate life-long disability in patients through appropriate early intervention, and it is imperative to develop new diagnostic methods for early detection of neurodevelopmental disorders. We examined the serum level of secretogranin II (SCG2) in pediatric patients to evaluate its potential role as a biomarker for neurodevelopmental disorders. A plasmonic immunosensor performing an enzyme-linked immunosorbent assay (ELISA) on a gold nanodot array was developed to detect SCG2 in small volumes of serum. This nanoplasmonic immunosensor combined with tyramide signal amplification was highly sensitive to detect SCG2 in only 5 μL serum samples. The analysis using the nanoplasmonic immunosensor revealed higher serum SCG2 levels in pediatric patients with developmental delay than in the control group. Overexpression or knockdown of SCG2 in hippocampal neurons significantly attenuated dendritic arborization and synaptic formation. These results suggest that dysregulated SCG2 expression impairs neural development. In conclusion, we developed a highly sensitive nanoplasmonic immunosensor to detect serum SCG2, a candidate biomarker for the early diagnosis of neurodevelopmental disorders.

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Visual Neural Development and Plasticity

Contemporary Psychology ◽

10.1037/020942 ◽

1982 ◽

Vol 27 (2) ◽

pp. 128-129

Author(s):

Donald E. Mitchell

Keyword(s):

Neural Development

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