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Advances in Neurodevelopmental Disorders (NDDs) Research
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Advances in Neurodevelopmental Disorders (NDDs) Research

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 33868

Special Issue Editors

Dr. Shilpa D. Kadam

E-Mail Website
Guest Editor
Translational Neuroscience, AXONIS Therapeutics Inc., Boston, MA 02111, USA
Interests: neurodevelopmental disorders; epilepsy; refractory seizures; ADHD; autism
Dr. Xin Tang

E-Mail Website1 Website2
Co-Guest Editor
Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
Interests: brain disease drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Advances in the identification and validation of various neurodevelopmental disorder (NDD) genes and biomarkers, together with the expansion of robust disease phenotype detection technologies and bioinformatics tools, have enabled molecular profiling and diagnosis for many NDDs and led to the identification of many novel molecular targets and pathways that may be targeted for treating patients. These discoveries have created new frontiers for investigators to conduct basic and translational research to investigate underlying molecular and systems neuroscience mechanisms to help develop novel therapeutic strategies as well as performance metrics for future pre-clinical research and clinical trial preparedness. Our understanding of the genetics of NDDs has deepened considerably over the past decade, contributing to the rapid emergence of opportunities for disease-modifying therapies by understanding the molecular mechanisms that drive pathogenesis. Therefore, we believe now is the right time for launching a special issue to highlight the ongoing basic and translational research focused on molecular and circuit mechanisms targeting disease modification in NDD.

This issue will be dedicated to original articles and reviews for Basic research and Translational/Preclinical research.

Dr. Shilpa D. Kadam
Dr. Xin Tang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • neurodevelopmental disorders (NDD)
  • early-life seizures
  • autism
  • intellectual disability
  • EEG
  • drug target
  • novel therapies
  • molecular mechanisms
  • systems neuroscience

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Published Papers (7 papers)

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Research

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15 pages, 3177 KiB  
Article
Na+/K+- and Mg2+-ATPases and Their Interaction with AMPA, NMDA and D2 Dopamine Receptors in an Animal Model of Febrile Seizures
by María Crespo, David Agustín León-Navarro and Mairena Martín
Int. J. Mol. Sci. 2022, 23(23), 14638; https://doi.org/10.3390/ijms232314638 - 24 Nov 2022
Cited by 5 | Viewed by 2061
Abstract
Febrile seizures (FS) are one of the most common seizure disorders in childhood which are classified into short and prolonged, depending on their duration. Short FS are usually considered as benign. However, epidemiological studies have shown an association between prolonged FS and temporal [...] Read more.
Febrile seizures (FS) are one of the most common seizure disorders in childhood which are classified into short and prolonged, depending on their duration. Short FS are usually considered as benign. However, epidemiological studies have shown an association between prolonged FS and temporal lobe epilepsy. The development of animal models of FS has been very useful to investigate the mechanisms and the consequences of FS. One of the most used, the “hair dryer model”, has revealed that prolonged FS may lead to temporal lobe epilepsy by altering neuronal function. Several pieces of evidence suggest that Na+/ K+-ATPase and Mg2+-ATPase may play a role in this epileptogenic process. In this work, we found that hyperthermia-induced seizures (HIS) significantly increased the activity of Na+/ K+-ATPase and Mg2+-ATPase five and twenty days after hyperthermic insult, respectively. These effects were diminished in response to AMPA, D2 dopamine A1 and A2A receptors activation, respectively. Furthermore, HIS also significantly increased the protein level of the AMPA subunit GluR1. Altogether, the increased Na+/ K+-ATPase and Mg2+-ATPase agree well with the presence of protective mechanisms. However, the reduction in ATPase activities in the presence of NMDA and AMPA suggest an increased propensity for epileptic events in adults. Full article
(This article belongs to the Special Issue Advances in Neurodevelopmental Disorders (NDDs) Research)
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16 pages, 5937 KiB  
Article
Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs
by Bumsoo Kim, Yongjun Koh, Hyunsu Do, Younghee Ju, Jong Bin Choi, Gahyang Cho, Han-Wook Yoo, Beom Hee Lee, Jinju Han, Jong-Eun Park and Yong-Mahn Han
Int. J. Mol. Sci. 2022, 23(22), 13861; https://doi.org/10.3390/ijms232213861 - 10 Nov 2022
Cited by 4 | Viewed by 3677
Abstract
Noonan syndrome (NS) is a genetic disorder mainly caused by gain-of-function mutations in Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Although diverse neurological manifestations are commonly diagnosed in NS patients, the mechanisms as to how SHP2 mutations induce the neurodevelopmental defects [...] Read more.
Noonan syndrome (NS) is a genetic disorder mainly caused by gain-of-function mutations in Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Although diverse neurological manifestations are commonly diagnosed in NS patients, the mechanisms as to how SHP2 mutations induce the neurodevelopmental defects associated with NS remain elusive. Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs). Although NS-COs develop normally in their appearance, single-cell transcriptomic analysis revealed an increase in the EN population and overexpression of cortical layer markers in NS-COs. Surprisingly, the EN subpopulation co-expressing the upper layer marker SATB2 and the deep layer maker CTIP2 was enriched in NS-COs during cortical development. In parallel with the developmental disruptions, NS-COs also exhibited reduced synaptic connectivity. Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity contribute to the neurological manifestations of NS. Full article
(This article belongs to the Special Issue Advances in Neurodevelopmental Disorders (NDDs) Research)
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15 pages, 6582 KiB  
Article
Knockout of Katnal2 Leads to Autism-like Behaviors and Developmental Delay in Zebrafish
by Jing Zheng, Fei Long, Xu Cao, Bo Xiong and Yu Li
Int. J. Mol. Sci. 2022, 23(15), 8389; https://doi.org/10.3390/ijms23158389 - 29 Jul 2022
Cited by 12 | Viewed by 3420
Abstract
KATNAL2 mutations have been associated with autism spectrum disorder (ASD) and other related neurodevelopmental disorders (NDDs) such as intellectual disability (ID) in several cohorts. KATNAL2 has been implicated in brain development, as it is required for ciliogenesis in Xenopus and is required for [...] Read more.
KATNAL2 mutations have been associated with autism spectrum disorder (ASD) and other related neurodevelopmental disorders (NDDs) such as intellectual disability (ID) in several cohorts. KATNAL2 has been implicated in brain development, as it is required for ciliogenesis in Xenopus and is required for dendritic arborization in mice. However, a causative relationship between the disruption of Katnal2 function and behavioral defects has not been established. Here, we generated a katnal2 null allele in zebrafish using CRISPR/Cas9-mediated genome editing and carried out morphological and behavioral characterizations. We observed that katnal2-/- embryos displayed delayed embryonic development especially during the convergence and extension (CE) movement. The hatched larvae showed reduced brain size and body length. In the behavioral tests, the katnal2-/- zebrafish exhibited reduced locomotor activity both in larvae and adults; increased nocturnal waking activity in larvae; and enhanced anxiety-like behavior, impaired social interaction, and reduced social cohesion in adults. These findings indicate an important role for katnal2 in development and behavior, providing an in vivo model to study the mechanisms underlying the ASD related to KATNAL2 mutations. Full article
(This article belongs to the Special Issue Advances in Neurodevelopmental Disorders (NDDs) Research)
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16 pages, 1663 KiB  
Article
A Novel Loss-of-Function SEMA3E Mutation in a Patient with Severe Intellectual Disability and Cognitive Regression
by Alyssa J. J. Paganoni, Federica Amoruso, Javier Porta Pelayo, Beatriz Calleja-Pérez, Valeria Vezzoli, Paolo Duminuco, Alessia Caramello, Roberto Oleari, Alberto Fernández-Jaén and Anna Cariboni
Int. J. Mol. Sci. 2022, 23(10), 5632; https://doi.org/10.3390/ijms23105632 - 18 May 2022
Cited by 5 | Viewed by 3412
Abstract
Intellectual disability (ID) is a neurological disorder arising from early neurodevelopmental defects. The underlying genetic and molecular mechanisms are complex, but are thought to involve, among others, alterations in genes implicated in axon guidance and/or neural circuit formation as demonstrated by studies on [...] Read more.
Intellectual disability (ID) is a neurological disorder arising from early neurodevelopmental defects. The underlying genetic and molecular mechanisms are complex, but are thought to involve, among others, alterations in genes implicated in axon guidance and/or neural circuit formation as demonstrated by studies on mouse models. Here, by combining exome sequencing with in silico analyses, we identified a patient affected by severe ID and cognitive regression, carrying a novel loss-of-function variant in the semaphorin 3E (SEMA3E) gene, which encodes for a key secreted cue that controls mouse brain development. By performing ad hoc in vitro and ex vivo experiments, we found that the identified variant impairs protein secretion and hampers the binding to both embryonic mouse neuronal cells and tissues. Further, we revealed SEMA3E expression during human brain development. Overall, our findings demonstrate the pathogenic impact of the identified SEMA3E variant and provide evidence that clinical neurological features of the patient might be due to a defective SEMA3E signaling in the brain. Full article
(This article belongs to the Special Issue Advances in Neurodevelopmental Disorders (NDDs) Research)
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20 pages, 1021 KiB  
Article
Shortened Infant Telomere Length Is Associated with Attention Deficit/Hyperactivity Disorder Symptoms in Children at Age Two Years: A Birth Cohort Study
by Cindy Pham, Regan Vryer, Martin O’Hely, Toby Mansell, David Burgner, Fiona Collier, Christos Symeonides, Mimi L. K. Tang, Peter Vuillermin, Lawrence Gray, Richard Saffery, Anne-Louise Ponsonby and on behalf of the Barwon Infant Study Investigator Group
Int. J. Mol. Sci. 2022, 23(9), 4601; https://doi.org/10.3390/ijms23094601 - 21 Apr 2022
Cited by 13 | Viewed by 4750
Abstract
Environmental factors can accelerate telomere length (TL) attrition. Shortened TL is linked to attention deficit/hyperactivity disorder (ADHD) symptoms in school-aged children. The onset of ADHD occurs as early as preschool-age, but the TL-ADHD association in younger children is unknown. We investigated associations between [...] Read more.
Environmental factors can accelerate telomere length (TL) attrition. Shortened TL is linked to attention deficit/hyperactivity disorder (ADHD) symptoms in school-aged children. The onset of ADHD occurs as early as preschool-age, but the TL-ADHD association in younger children is unknown. We investigated associations between infant TL and ADHD symptoms in children and assessed environmental factors as potential confounders and/or mediators of this association. Relative TL was measured by quantitative polymerase chain reaction in cord and 12-month blood in the birth cohort study, the Barwon Infant Study. Early life environmental factors collected antenatally to two years were used to measure confounding. ADHD symptoms at age two years were evaluated by the Child Behavior Checklist Attention Problems (AP) and the Attention Deficit/Hyperactivity Problems (ADHP). Associations between early life environmental factors on TL or ADHD symptoms were assessed using multivariable regression models adjusted for relevant factors. Telomere length at 12 months (TL12), but not at birth, was inversely associated with AP (β = −0.56; 95% CI (−1.13, 0.006); p = 0.05) and ADHP (β = −0.66; 95% CI (−1.11, −0.21); p = 0.004). Infant secondhand smoke exposure at one month was independently associated with shorter TL12 and also higher ADHD symptoms. Further work is needed to elucidate the mechanisms that influence TL attrition and early neurodevelopment. Full article
(This article belongs to the Special Issue Advances in Neurodevelopmental Disorders (NDDs) Research)
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Review

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30 pages, 3447 KiB  
Review
Clocking Epilepsies: A Chronomodulated Strategy-Based Therapy for Rhythmic Seizures
by Sha Sun and Han Wang
Int. J. Mol. Sci. 2023, 24(4), 4223; https://doi.org/10.3390/ijms24044223 - 20 Feb 2023
Cited by 8 | Viewed by 4757
Abstract
Epilepsy is a neurological disorder characterized by hypersynchronous recurrent neuronal activities and seizures, as well as loss of muscular control and sometimes awareness. Clinically, seizures have been reported to display daily variations. Conversely, circadian misalignment and circadian clock gene variants contribute to epileptic [...] Read more.
Epilepsy is a neurological disorder characterized by hypersynchronous recurrent neuronal activities and seizures, as well as loss of muscular control and sometimes awareness. Clinically, seizures have been reported to display daily variations. Conversely, circadian misalignment and circadian clock gene variants contribute to epileptic pathogenesis. Elucidation of the genetic bases of epilepsy is of great importance because the genetic variability of the patients affects the efficacies of antiepileptic drugs (AEDs). For this narrative review, we compiled 661 epilepsy-related genes from the PHGKB and OMIM databases and classified them into 3 groups: driver genes, passenger genes, and undetermined genes. We discuss the potential roles of some epilepsy driver genes based on GO and KEGG analyses, the circadian rhythmicity of human and animal epilepsies, and the mutual effects between epilepsy and sleep. We review the advantages and challenges of rodents and zebrafish as animal models for epileptic studies. Finally, we posit chronomodulated strategy-based chronotherapy for rhythmic epilepsies, integrating several lines of investigation for unraveling circadian mechanisms underpinning epileptogenesis, chronopharmacokinetic and chronopharmacodynamic examinations of AEDs, as well as mathematical/computational modeling to help develop time-of-day-specific AED dosing schedules for rhythmic epilepsy patients. Full article
(This article belongs to the Special Issue Advances in Neurodevelopmental Disorders (NDDs) Research)
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33 pages, 2055 KiB  
Review
Epilepsy Characteristics in Neurodevelopmental Disorders: Research from Patient Cohorts and Animal Models Focusing on Autism Spectrum Disorder
by Sukanya Chakraborty, Rrejusha Parayil, Shefali Mishra, Upendra Nongthomba and James P. Clement
Int. J. Mol. Sci. 2022, 23(18), 10807; https://doi.org/10.3390/ijms231810807 - 16 Sep 2022
Cited by 14 | Viewed by 9934
Abstract
Epilepsy, a heterogeneous group of brain-related diseases, has continued to significantly burden society and families. Epilepsy comorbid with neurodevelopmental disorders (NDDs) is believed to occur due to multifaceted pathophysiological mechanisms involving disruptions in the excitation and inhibition (E/I) balance impeding widespread functional neuronal [...] Read more.
Epilepsy, a heterogeneous group of brain-related diseases, has continued to significantly burden society and families. Epilepsy comorbid with neurodevelopmental disorders (NDDs) is believed to occur due to multifaceted pathophysiological mechanisms involving disruptions in the excitation and inhibition (E/I) balance impeding widespread functional neuronal circuitry. Although the field has received much attention from the scientific community recently, the research has not yet translated into actionable therapeutics to completely cure epilepsy, particularly those comorbid with NDDs. In this review, we sought to elucidate the basic causes underlying epilepsy as well as those contributing to the association of epilepsy with NDDs. Comprehensive emphasis is put on some key neurodevelopmental genes implicated in epilepsy, such as MeCP2, SYNGAP1, FMR1, SHANK1-3 and TSC1, along with a few others, and the main electrophysiological and behavioral deficits are highlighted. For these genes, the progress made in developing appropriate and valid rodent models to accelerate basic research is also detailed. Further, we discuss the recent development in the therapeutic management of epilepsy and provide a briefing on the challenges and caveats in identifying and testing species-specific epilepsy models. Full article
(This article belongs to the Special Issue Advances in Neurodevelopmental Disorders (NDDs) Research)
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