Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Alt...Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Although these conditions differ in clinical presentation, they share fundamental pathological features that may stem from abnormal mitochondrial dynamics and impaired autophagic clearance, which contribute to redox imbalance and oxidative stress in neurons. This review aimed to elucidate the relationship between mitochondrial dynamics dysfunction and neurodevelopmental disorders. Mitochondria are highly dynamic organelles that undergo continuous fusion and fission to meet the substantial energy demands of neural cells. Dysregulation of these processes, as observed in certain neurodevelopmental disorders, causes accumulation of damaged mitochondria, exacerbating oxidative damage and impairing neuronal function. The phosphatase and tensin homolog-induced putative kinase 1/E3 ubiquitin-protein ligase pathway is crucial for mitophagy, the process of selectively removing malfunctioning mitochondria. Mutations in genes encoding mitochondrial fusion proteins have been identified in autism spectrum disorders, linking disruptions in the fusion-fission equilibrium to neurodevelopmental impairments. Additionally, animal models of Rett syndrome have shown pronounced defects in mitophagy, reinforcing the notion that mitochondrial quality control is indispensable for neuronal health. Clinical studies have highlighted the importance of mitochondrial disturbances in neurodevelopmental disorders. In autism spectrum disorders, elevated oxidative stress markers and mitochondrial DNA deletions indicate compromised mitochondrial function. Attention-deficit/hyperactivity disorder has also been associated with cognitive deficits linked to mitochondrial dysfunction and oxidative stress. Moreover, induced pluripotent stem cell models derived from patients with Rett syndrome have shown impaired mitochondrial dynamics and heightened vulnerability to oxidative injury, suggesting the role of defective mitochondrial homeostasis in these disorders. From a translational standpoint, multiple therapeutic approaches targeting mitochondrial pathways show promise. Interventions aimed at preserving normal fusion-fission cycles or enhancing mitophagy can reduce oxidative damage by limiting the accumulation of defective mitochondria. Pharmacological modulation of mitochondrial permeability and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, an essential regulator of mitochondrial biogenesis, may also ameliorate cellular energy deficits. Identifying early biomarkers of mitochondrial impairment is crucial for precision medicine, since it can help clinicians tailor interventions to individual patient profiles and improve prognoses. Furthermore, integrating mitochondria-focused strategies with established therapies, such as antioxidants or behavioral interventions, may enhance treatment efficacy and yield better clinical outcomes. Leveraging these pathways could open avenues for regenerative strategies, given the influence of mitochondria on neuronal repair and plasticity. In conclusion, this review indicates mitochondrial homeostasis as a unifying therapeutic axis within neurodevelopmental pathophysiology. Disruptions in mitochondrial dynamics and autophagic clearance converge on oxidative stress, and researchers should prioritize validating these interventions in clinical settings to advance precision medicine and enhance outcomes for individuals affected by neurodevelopmental disorders.展开更多
Neurodevelopmental processes represent a finely tuned interplay between genetic and environmental factors,shaping the dynamic landscape of the developing brain.A major component of the developing brain that enables th...Neurodevelopmental processes represent a finely tuned interplay between genetic and environmental factors,shaping the dynamic landscape of the developing brain.A major component of the developing brain that enables this dynamic is the white matter(WM),known to be affected in neurodevelopmental disorders(NDDs)(Rokach et al.,2024).WM formation is mediated by myelination,a multifactorial process driven by neuro-glia interactions dependent on proper neuronal functionality(Simons and Trajkovic,2006).Another key aspect of neurodevelopmental abnormalities involves neuronal dynamics and function,with recent advances significantly enhancing our understanding of both neuronal and glial mitochondrial function(Devine and Kittler,2018;Rojas-Charry et al.,2021).Energy homeostasis in neurons,attributed largely to mitochondrial function,is critical for proper functionality and interactions with oligodendrocytes(OLs),the cells forming myelin in the brain’s WM.We herein discuss the interplay between these processes and speculate on potential dysfunction in NDDs.展开更多
Neuroinflammation is the primary driver and signature of many neurodevelopmental disorders.However,because neurodevelopmental disorders caused by neuroinflammation are difficult to detect at the early stage,their prog...Neuroinflammation is the primary driver and signature of many neurodevelopmental disorders.However,because neurodevelopmental disorders caused by neuroinflammation are difficult to detect at the early stage,their progression remains unclear.To date,neither animal experiments nor in vitro models have uncovered their early developmental characteristics caused by neuroinflammation.In this study,we developed a neurovascular-unit-on-a-chip(NVU-on-a-chip)to model inflammation-induced neurodevelopmental disorders.With the chip,dynamic visualization of the progression caused by neuroinflammation was clearly demonstrated,and the changes in angiogenesis and neural differentiation under neuroinflammation were replicated.In addition,the activation of astrocytes and damage to neurons and capillaries at the early stage of neurodevelopmental disorders were observed.The results revealed for the first time the structural disruption of the neurovascular units and the neurovascular coupling failure caused by neuroinflammation.Furthermore,the outcomes of anti-inflammatory intervention using ibuprofen were preliminarily demonstrated.This work provides insights into the early progression of neurodevelopmental disorders caused by neuroinflammation and offers a platform for the development of therapeutic strategies for neuroinflammation.展开更多
Critical periods(CPs)are defined as postnatal developmental windows during which brain circuits exhibit heightened sensitivity to altered experiences or sensory inputs,particularly during brain development in humans a...Critical periods(CPs)are defined as postnatal developmental windows during which brain circuits exhibit heightened sensitivity to altered experiences or sensory inputs,particularly during brain development in humans and animals.During the CP,experience-induced refinements of neural connections are crucial for establishing adaptive and mature brain functions,and aberrant CPs are often accompanied by many neurodevelopmental disorders(NDDs),including autism spectrum disorders and schizophrenia.Understanding neural mechanisms underlying the CP regulation is key to delineating the etiology of NDDs caused by abnormal postnatal neurodevelopment.Recent evidence from studies using innovative experimental tools has continuously revisited the inhibition-gating theory of CP to systematically elucidate the differential roles of distinct inhibitory circuits.Here,we provide a comprehensive review of classical experimental findings and emerging inhibitory-circuit regulation mechanisms of the CP,and further discuss how aberrant CP plasticity is associated with NDDs.展开更多
Maternal health during pregnancy has a direct impact on the risk and severity of neurodevelopmental disorders(NDDs)in the offspring,especially in the case of drug exposure.However,little progress has been made to asse...Maternal health during pregnancy has a direct impact on the risk and severity of neurodevelopmental disorders(NDDs)in the offspring,especially in the case of drug exposure.However,little progress has been made to assess the risk of drug exposure during pregnancy due to ethical constraints and drug use factors.We collected and manually curated sub-pathways and pathways(sub-/pathways)and drug information to propose an analytical framework for predicting drug candidates.This framework linked sub-/pathway activity and drug response scores derived from gene transcription data and was applied to human fetal brain development and six NDDs.Further,specific and pleiotropic sub-/pathways/drugs were identified using entropy,and sex bias was analyzed in conjunction with logistic regression and random forest models.We identified 19 disorder-associated and 256 regionally pleiotropic and specific candidate drugs that targeted risk sub-/pathways in NDDs,showing temporal or spatial changes across fetal development.Moreover,5443 differential drug-sub-/pathways exhibited sex-biased differences after filling in the gender labels.A user-friendly NDDP visualization website(https://ndd-lab.shinyapps.io/NDDP)was developed to allow researchers and clinicians to access and retrieve data easily.Our framework overcame data gaps and identified numerous pleiotropic and specific candidates across six disorders and fetal developmental trajectories.This could significantly contribute to drug discovery during pregnancy and can be applied to a wide range of traits.展开更多
Neurodevelopmental disorders are characterized by an abnormal development of the central nervous system, leading to a myriad of symptoms and diseases, including intellectual disability, attention deficits, impairments...Neurodevelopmental disorders are characterized by an abnormal development of the central nervous system, leading to a myriad of symptoms and diseases, including intellectual disability, attention deficits, impairments in learning and memory, speech disorders and repetitive behavior （Telias and Ben-Yosef, 2014）. Common major neurodevelopmental disorders include autism and autism spectrum disorders （ASDs）, fragile X syndrome （FXS）, Down syndrome （DS）, and Rett syndrome （RTT）. They can be collectively described as disorders in which the plasticity of the brain has been severely impaired. The concept of plasticity refers to the brain＇s ability to adapt to and process new information and react accordingly, and it can be classified into three categories： a） molecular plasticity, whenever specific receptors, ion channels, enzymes,展开更多
Mice use ultrasonic vocalizations(USVs)to communicate each other and to convey their emotional state.USVs have been greatly characterized in specific life phases and contexts,such as mother isolation-induced USVs for ...Mice use ultrasonic vocalizations(USVs)to communicate each other and to convey their emotional state.USVs have been greatly characterized in specific life phases and contexts,such as mother isolation-induced USVs for pups or female-induced USVs for male mice during courtship.USVs can be acquired by means of specific tools and later analyzed on the base of both quantitative and qualitative parameters.Indeed,different ultrasonic call categories exist and have already been defined.The understanding of different calls meaning is still missing,and it will represent an essential step forward in the field of USVs.They have long been studied in the ethological context,but recently they emerged as a precious instrument to study pathologies characterized by deficits in communication,in particular neurodevelopmental disorders(NDDs),such as autism spectrum disorders.This review covers the topics of USVs characteristics in mice,contexts for USVs emission and factors that modulate their expression.A particular focus will be devoted to mouse USVs in the context of NDDs.Indeed,several NDDs murine models exist and an intense study of USVs is currently in progress,with the aim of both performing an early diagnosis and to find a pharmacological/behavioral intervention to improve patients’quality of life.展开更多
There is a complex relationship between sleep disorders and childhood neurodevelopmental,emotional,behavioral and intellectual disorders(NDEBID).NDEBID include several conditions such as attention deficit/hyperactivit...There is a complex relationship between sleep disorders and childhood neurodevelopmental,emotional,behavioral and intellectual disorders(NDEBID).NDEBID include several conditions such as attention deficit/hyperactivity disorder,autism spectrum disorder,cerebral palsy,epilepsy and learning(intellectual)disorders.Up to 75%of children and young people(CYP)with NDEBID are known to experience different types of insomnia,compared to 3%to 36%in normally developing population.Sleep disorders affect 15%to 19%of adolescents with no disability,in comparison with 26%to 36%among CYP with moderate learning disability(LD)and 44%among those with severe LD.Chronic sleep deprivation is associated with significant risks of behavioural problems,impaired cognitive development and learning abilities,poor memory,mood disorders and school problems.It also increases the risk of other health outcomes,such as obesity and metabolic consequences,significantly impacting on the wellbeing of other family members.This narrative review of the extant literature provides a brief overview of sleep physiology,aetiology,classification and prevalence of sleep disorders among CYP with NDEBIDs.It outlines various strategies for the management,including parenting training/psychoeducation,use of cognitive-behavioral strategies and pharmacotherapy.Practical management including assessment,investigations,care plan formulation and follow-up are outlined in a flow chart.展开更多
Neurodevelopmental disorders are a group of conditions classified together by the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders which include intellectual disability,communication di...Neurodevelopmental disorders are a group of conditions classified together by the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders which include intellectual disability,communication disorders,autism spectrum disorder,attention-deficit/hyperactivity disorder,specific learning disorder(SLD),and motor disorders.SLD is present in many students,who exhibit significant difficulties in the acquisition of reading,written expression,and mathematics,mostly due to problems with executive functions(EF).The present study is a review of the current situation of neurodevelopmental disorders and SLD focusing on the benefits of the response to intervention model(RtI),which allows the combination of evaluation and intervention processes.It also addresses the key role of EF.The importance of adapting RtI to new possibilities such as the use of virtual reality is discussed and a theoretical framework for carrying that out is provided.展开更多
Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes,affecting individuals worldwide.While the subject has been heavily researched,current treatment options r...Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes,affecting individuals worldwide.While the subject has been heavily researched,current treatment options relate mostly to alleviating symptoms,rather than targeting the altered genome itself.In this review,we address the neurogenetic basis of neurodevelopmental disorders,genetic tools that are enabling precision research of these disorders in animal models,and postnatal gene-therapy approaches for neurodevelopmental disorders derived from preclinical studies in the laboratory.展开更多
Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 N...Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 NDD-related genes in 3,195 Chinese probands with neurodevelopmental phenotypes and identify 2,522 putative functional mutations consisting of 137 de novo mutations(DNMs)in 86 genes and 2,385 rare inherited mutations(RIMs)with 22 X-linked hemizygotes in 13 genes,2 homozygous mutations in 2 genes and 23 compound heterozygous mutations in 10 genes.Furthermore,the DNMs of16,807 probands with NDDs are retrieved from public datasets and combine in an integrated analysis with the mutation data of our Chinese NDD probands by taking 3,582 in-house controls of Chinese origin as background.We prioritize 26 novel candidate genes.Notably,six of these genes d ITSN1,UBR3,CADM1,RYR3,FLNA,and PLXNA3 d preferably contribute to autism spectrum disorders(ASDs),as demonstrated by high co-expression and/or interaction with ASD genes confirmed via rescue experiments in a mouse model.Importantly,these genes are differentially expressed in the ASD cortex in a significant manner and involved in ASD-associated networks.Together,our study expands the genetic spectrum of Chinese NDDs,further facilitating both basic and translational research.展开更多
Biological entities are involved in complicated and complex connections;hence,discovering biological information using network biology ideas is critical.In the past few years,network biology has emerged as an integrat...Biological entities are involved in complicated and complex connections;hence,discovering biological information using network biology ideas is critical.In the past few years,network biology has emerged as an integrative and systems-level approach for understanding and interpreting these complex interactions.Biological network analysis is one method for reducing enormous data sets to clinically useful knowledge for disease diagnosis,prognosis,and treatment.The network of biological entities can help us predict drug targets for several diseases.The drug targets identified through the systems biology approach help in targeting the essential biological pathways that contribute to the progression and development of the disease.The novel strategical approach of system biologyassisted pharmacology coupled with computer-aided drug discovery(CADD)can help drugs fight multifactorial diseases efficiently.In the present review,we have summarized the role and application of network biology for not only unfolding the mechanism of complex neurodevelopmental disorders but also identifying important drug targets for diseases like ADHD,Autism,Epilepsy,and Intellectual Disability.Systems biology has emerged as a promising approach to identifying drug targets and aiming for targeted drug discovery for the precise treatment of neurodevelopmental disorders.展开更多
Kelch-like family member 17(KLHL17)is predominantly expressed in the brain and plays a crucial role in neuronal development and function,deletions and/or mutations in KLHL17 have been linked to neurodevelopmental diso...Kelch-like family member 17(KLHL17)is predominantly expressed in the brain and plays a crucial role in neuronal development and function,deletions and/or mutations in KLHL17 have been linked to neurodevelopmental disorders in humans,e.g.,intellectual disability,autism spectrum disorder,and infantile spasms,but the etiology and pathogenesis remain largely enigmatic.1,2 As a member of the family of the Kelch proteins,KLHL17 contains an N-terminal BTB/POZ domain followed by a BACK domain and four to six tandem Kelch motifs at the C-terminal region(Fig.S1A).1,3 Previously,we identified a novel de novo variant in KLHL17(c.701C>T;p.P234L)in a cohort of 225 Chinese children with developmental delay/intellectual disability based on whole-exome sequencing(1/225),the mutation located in the BACK domain,a very high conversed region(Fig.S1B),and the affected boy presented with developmental delay,intellectual disability,hypotonia,and abnormal brainstem auditory evoked potential signal.4 The finding may offer a new clue to investigate the molecular pathogenesis of KLHL17 gene in neurodevelopmental disorders.展开更多
Dear Editor,Neurodevelopmental disorders(NDD)are a group of diseases with high phenotypic heterogeneity characterized by inability in cognition,communication,psychological skills,and motor development.The common types...Dear Editor,Neurodevelopmental disorders(NDD)are a group of diseases with high phenotypic heterogeneity characterized by inability in cognition,communication,psychological skills,and motor development.The common types of NDDs include autism spectrum disorder(ASD),attention-deficit/hyperactivity disorder(ADHD),epilepsy,schizophrenia,etc.(Parenti et al.,2020).展开更多
Neurodevelopmental disorders(NDDs)are a group of highly heterogeneous diseases that affect children’s social,cognitive,and emotional functioning.The etiology is complicated with genetic factors playing an important r...Neurodevelopmental disorders(NDDs)are a group of highly heterogeneous diseases that affect children’s social,cognitive,and emotional functioning.The etiology is complicated with genetic factors playing an important role.During the past decade,large-scale whole exome sequencing(WES)and whole genome sequencing(WGS)have vastly advanced the genetic findings of NDDs.Various forms of variants have been reported to contribute to NDDs,such as de novo mutations(DNMs),copy number variations(CNVs),rare inherited variants(RIVs),and common variation.By far,over 200 high-risk NDD genes have been identified,which are involved in biological processes including synaptic function,transcriptional and epigenetic regulation.In addition,monogenic,oligogenic,polygenetic,and omnigenic models have been proposed to explain the genetic architecture of NDDs.However,the majority of NDD patients still do not have a definitive genetic diagnosis.In the future,more types of risk factors,as well as noncoding variants,are await to be identified,and including their interplay mechanisms are key to resolving the etiology and heterogeneity of NDDs.展开更多
The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis,regulating various physiological processes.In recent years,the impacts of the gut microbiota on neurodevelopment throu...The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis,regulating various physiological processes.In recent years,the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated.The gut microbiota is commonly considered to regulate neurodevelopment through three pathways,the immune pathway,the neuronal pathway,and the endocrine/systemic pathway,with overlaps and crosstalks in between.Accumulating studies have identified the role of the microbiota-gut-brain axis in neurodevelopmental disorders including autism spectrum disorder,attention deficit hyperactivity disorder,and Rett Syndrome.Numerous researchers have examined the physiological and pathophysiological mechanisms influenced by the gut microbiota in neurodevelopmental disorders(NDDs).This review aims to provide a comprehensive overview of advancements in research pertaining to the microbiota-gut-brain axis in NDDs.Furthermore,we analyzed both the current state of research progress and discuss future perspectives in this field.展开更多
Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism ...Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.展开更多
Background Formation of protein complexes across synapses is a critical process in neurodevelopment,having direct implications on brain function and animal behavior.Here,we present the understanding,importance,and pot...Background Formation of protein complexes across synapses is a critical process in neurodevelopment,having direct implications on brain function and animal behavior.Here,we present the understanding,importance,and potential impact of a newly found regulator of such a key interaction.Data sources A systematic search of the literature was conducted on PubMed(Medline),Embase,and Central-Cochrane Database.Results Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins(MDGAs)were recently discovered to regulate synaptic development and transmission via suppression of neurexins-neuroligins transsynaptic complex formation.MDGAs also regulate axonal migration and outgrowth.In the context of their physiological role,we begin to consider the potential links to the etiology of certain neurodevelopmental disorders.We present the gene expression and protein structure of MDGAs and discuss recent progress in our understanding of the neurobiological role of MDGAs to explore its potential as a therapeutic target.Conclusion MDGAs play a key role in neuron migration,axon guidance and synapse development,as well as in regulating brain excitation and inhibition balance.展开更多
‘Neurodevelopmental disorders’comprise a group of congenital or acquired longterm conditions that are attributed to disturbance of the brain and or neuromuscular system and create functional limitations,including au...‘Neurodevelopmental disorders’comprise a group of congenital or acquired longterm conditions that are attributed to disturbance of the brain and or neuromuscular system and create functional limitations,including autism spectrum disorder,attention deficit/hyperactivity disorder,tic disorder/Tourette’s syndrome,developmental language disorders and intellectual disability.Cerebral palsy and epilepsy are often associated with these conditions within the broader framework of paediatric neurodisability.Co-occurrence with each other and with other mental health disorders including anxiety and mood disorders and behavioural disturbance is often the norm.Together these are referred to as neurodevelopmental,emotional,behavioural,and intellectual disorders(NDEBIDs)in this paper.Varying prevalence rates for NDEBID have been reported in developed countries,up to 15%,based on varying methodologies and definitions.NDEBIDs are commonly managed by either child health paediatricians or child/adolescent mental health(CAMH)professionals,working within multidisciplinary teams alongside social care,education,allied healthcare practitioners and voluntary sector.Fragmented services are common problems for children and young people with multi-morbidity,and often complicated by subthreshold diagnoses.Despite repeated reviews,limited consensus among clinicians about classification of the various NDEBIDs may hamper service improvement based upon research.The recently developed“Mental,Behavioural and Neurodevelopmental disorder”chapter of the International Classification of Diseases-11 offers a way forward.In this narrative review we search the extant literature and discussed a brief overview of the aetiology and prevalence of NDEBID,enumerate common problems associated with current classification systems and provide recommendations for a more integrated approach to the nosology and clinical care of these related conditions.展开更多
文摘Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Although these conditions differ in clinical presentation, they share fundamental pathological features that may stem from abnormal mitochondrial dynamics and impaired autophagic clearance, which contribute to redox imbalance and oxidative stress in neurons. This review aimed to elucidate the relationship between mitochondrial dynamics dysfunction and neurodevelopmental disorders. Mitochondria are highly dynamic organelles that undergo continuous fusion and fission to meet the substantial energy demands of neural cells. Dysregulation of these processes, as observed in certain neurodevelopmental disorders, causes accumulation of damaged mitochondria, exacerbating oxidative damage and impairing neuronal function. The phosphatase and tensin homolog-induced putative kinase 1/E3 ubiquitin-protein ligase pathway is crucial for mitophagy, the process of selectively removing malfunctioning mitochondria. Mutations in genes encoding mitochondrial fusion proteins have been identified in autism spectrum disorders, linking disruptions in the fusion-fission equilibrium to neurodevelopmental impairments. Additionally, animal models of Rett syndrome have shown pronounced defects in mitophagy, reinforcing the notion that mitochondrial quality control is indispensable for neuronal health. Clinical studies have highlighted the importance of mitochondrial disturbances in neurodevelopmental disorders. In autism spectrum disorders, elevated oxidative stress markers and mitochondrial DNA deletions indicate compromised mitochondrial function. Attention-deficit/hyperactivity disorder has also been associated with cognitive deficits linked to mitochondrial dysfunction and oxidative stress. Moreover, induced pluripotent stem cell models derived from patients with Rett syndrome have shown impaired mitochondrial dynamics and heightened vulnerability to oxidative injury, suggesting the role of defective mitochondrial homeostasis in these disorders. From a translational standpoint, multiple therapeutic approaches targeting mitochondrial pathways show promise. Interventions aimed at preserving normal fusion-fission cycles or enhancing mitophagy can reduce oxidative damage by limiting the accumulation of defective mitochondria. Pharmacological modulation of mitochondrial permeability and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, an essential regulator of mitochondrial biogenesis, may also ameliorate cellular energy deficits. Identifying early biomarkers of mitochondrial impairment is crucial for precision medicine, since it can help clinicians tailor interventions to individual patient profiles and improve prognoses. Furthermore, integrating mitochondria-focused strategies with established therapies, such as antioxidants or behavioral interventions, may enhance treatment efficacy and yield better clinical outcomes. Leveraging these pathways could open avenues for regenerative strategies, given the influence of mitochondria on neuronal repair and plasticity. In conclusion, this review indicates mitochondrial homeostasis as a unifying therapeutic axis within neurodevelopmental pathophysiology. Disruptions in mitochondrial dynamics and autophagic clearance converge on oxidative stress, and researchers should prioritize validating these interventions in clinical settings to advance precision medicine and enhance outcomes for individuals affected by neurodevelopmental disorders.
文摘Neurodevelopmental processes represent a finely tuned interplay between genetic and environmental factors,shaping the dynamic landscape of the developing brain.A major component of the developing brain that enables this dynamic is the white matter(WM),known to be affected in neurodevelopmental disorders(NDDs)(Rokach et al.,2024).WM formation is mediated by myelination,a multifactorial process driven by neuro-glia interactions dependent on proper neuronal functionality(Simons and Trajkovic,2006).Another key aspect of neurodevelopmental abnormalities involves neuronal dynamics and function,with recent advances significantly enhancing our understanding of both neuronal and glial mitochondrial function(Devine and Kittler,2018;Rojas-Charry et al.,2021).Energy homeostasis in neurons,attributed largely to mitochondrial function,is critical for proper functionality and interactions with oligodendrocytes(OLs),the cells forming myelin in the brain’s WM.We herein discuss the interplay between these processes and speculate on potential dysfunction in NDDs.
基金supported by the National Key R&D Program of China(No.2018AAA0100300)the National Natural Science Foundation of China(Nos.82072018,82274375,and 82402490)+5 种基金the Anhui Provincial Science and Technology Major Project(No.202203a07020006)the Strategic Priority Research Program(C)of the Chinese Academy of Sciences(CAS)(No.XDC07040200)the Key R&D Program of Anhui Province(No.2022e07020012)the Natural Science Foundation of Anhui Province(No.2208085QH256)the Fundamental Research Funds for the Central Universities(No.WK2100000042)the China Postdoctoral Science Foundation(No.2022M713055).
文摘Neuroinflammation is the primary driver and signature of many neurodevelopmental disorders.However,because neurodevelopmental disorders caused by neuroinflammation are difficult to detect at the early stage,their progression remains unclear.To date,neither animal experiments nor in vitro models have uncovered their early developmental characteristics caused by neuroinflammation.In this study,we developed a neurovascular-unit-on-a-chip(NVU-on-a-chip)to model inflammation-induced neurodevelopmental disorders.With the chip,dynamic visualization of the progression caused by neuroinflammation was clearly demonstrated,and the changes in angiogenesis and neural differentiation under neuroinflammation were replicated.In addition,the activation of astrocytes and damage to neurons and capillaries at the early stage of neurodevelopmental disorders were observed.The results revealed for the first time the structural disruption of the neurovascular units and the neurovascular coupling failure caused by neuroinflammation.Furthermore,the outcomes of anti-inflammatory intervention using ibuprofen were preliminarily demonstrated.This work provides insights into the early progression of neurodevelopmental disorders caused by neuroinflammation and offers a platform for the development of therapeutic strategies for neuroinflammation.
基金supported by grants from the National Natural Science Foundation of China(32130043 to X.Z.)the Scientific&Technological Innovation(STI)2030-Major Project(2022ZD0204900 to X.Z.)+1 种基金the National Natural Science Foundation of China(32400870 to Z.S.)the Fundamental Research Funds for the Central Universities(2243300002 to Z.S.).
文摘Critical periods(CPs)are defined as postnatal developmental windows during which brain circuits exhibit heightened sensitivity to altered experiences or sensory inputs,particularly during brain development in humans and animals.During the CP,experience-induced refinements of neural connections are crucial for establishing adaptive and mature brain functions,and aberrant CPs are often accompanied by many neurodevelopmental disorders(NDDs),including autism spectrum disorders and schizophrenia.Understanding neural mechanisms underlying the CP regulation is key to delineating the etiology of NDDs caused by abnormal postnatal neurodevelopment.Recent evidence from studies using innovative experimental tools has continuously revisited the inhibition-gating theory of CP to systematically elucidate the differential roles of distinct inhibitory circuits.Here,we provide a comprehensive review of classical experimental findings and emerging inhibitory-circuit regulation mechanisms of the CP,and further discuss how aberrant CP plasticity is associated with NDDs.
基金supported by the National Natural Science Foundation of China[81701350 and 31671252]the Health Technology Plan of Zhejiang Province[2023RC205].
文摘Maternal health during pregnancy has a direct impact on the risk and severity of neurodevelopmental disorders(NDDs)in the offspring,especially in the case of drug exposure.However,little progress has been made to assess the risk of drug exposure during pregnancy due to ethical constraints and drug use factors.We collected and manually curated sub-pathways and pathways(sub-/pathways)and drug information to propose an analytical framework for predicting drug candidates.This framework linked sub-/pathway activity and drug response scores derived from gene transcription data and was applied to human fetal brain development and six NDDs.Further,specific and pleiotropic sub-/pathways/drugs were identified using entropy,and sex bias was analyzed in conjunction with logistic regression and random forest models.We identified 19 disorder-associated and 256 regionally pleiotropic and specific candidate drugs that targeted risk sub-/pathways in NDDs,showing temporal or spatial changes across fetal development.Moreover,5443 differential drug-sub-/pathways exhibited sex-biased differences after filling in the gender labels.A user-friendly NDDP visualization website(https://ndd-lab.shinyapps.io/NDDP)was developed to allow researchers and clinicians to access and retrieve data easily.Our framework overcame data gaps and identified numerous pleiotropic and specific candidates across six disorders and fetal developmental trajectories.This could significantly contribute to drug discovery during pregnancy and can be applied to a wide range of traits.
文摘Neurodevelopmental disorders are characterized by an abnormal development of the central nervous system, leading to a myriad of symptoms and diseases, including intellectual disability, attention deficits, impairments in learning and memory, speech disorders and repetitive behavior （Telias and Ben-Yosef, 2014）. Common major neurodevelopmental disorders include autism and autism spectrum disorders （ASDs）, fragile X syndrome （FXS）, Down syndrome （DS）, and Rett syndrome （RTT）. They can be collectively described as disorders in which the plasticity of the brain has been severely impaired. The concept of plasticity refers to the brain＇s ability to adapt to and process new information and react accordingly, and it can be classified into three categories： a） molecular plasticity, whenever specific receptors, ion channels, enzymes,
基金supported by Research Grant from the University of Brescia(to Memo M).
文摘Mice use ultrasonic vocalizations(USVs)to communicate each other and to convey their emotional state.USVs have been greatly characterized in specific life phases and contexts,such as mother isolation-induced USVs for pups or female-induced USVs for male mice during courtship.USVs can be acquired by means of specific tools and later analyzed on the base of both quantitative and qualitative parameters.Indeed,different ultrasonic call categories exist and have already been defined.The understanding of different calls meaning is still missing,and it will represent an essential step forward in the field of USVs.They have long been studied in the ethological context,but recently they emerged as a precious instrument to study pathologies characterized by deficits in communication,in particular neurodevelopmental disorders(NDDs),such as autism spectrum disorders.This review covers the topics of USVs characteristics in mice,contexts for USVs emission and factors that modulate their expression.A particular focus will be devoted to mouse USVs in the context of NDDs.Indeed,several NDDs murine models exist and an intense study of USVs is currently in progress,with the aim of both performing an early diagnosis and to find a pharmacological/behavioral intervention to improve patients’quality of life.
文摘There is a complex relationship between sleep disorders and childhood neurodevelopmental,emotional,behavioral and intellectual disorders(NDEBID).NDEBID include several conditions such as attention deficit/hyperactivity disorder,autism spectrum disorder,cerebral palsy,epilepsy and learning(intellectual)disorders.Up to 75%of children and young people(CYP)with NDEBID are known to experience different types of insomnia,compared to 3%to 36%in normally developing population.Sleep disorders affect 15%to 19%of adolescents with no disability,in comparison with 26%to 36%among CYP with moderate learning disability(LD)and 44%among those with severe LD.Chronic sleep deprivation is associated with significant risks of behavioural problems,impaired cognitive development and learning abilities,poor memory,mood disorders and school problems.It also increases the risk of other health outcomes,such as obesity and metabolic consequences,significantly impacting on the wellbeing of other family members.This narrative review of the extant literature provides a brief overview of sleep physiology,aetiology,classification and prevalence of sleep disorders among CYP with NDEBIDs.It outlines various strategies for the management,including parenting training/psychoeducation,use of cognitive-behavioral strategies and pharmacotherapy.Practical management including assessment,investigations,care plan formulation and follow-up are outlined in a flow chart.
基金Supported by Ministry of Sciences and Innovation I+D+i Project,No.PID2019-107201GB-100Principality of Asturias,No.FCGRUPIN-IDI/2018/000199.
文摘Neurodevelopmental disorders are a group of conditions classified together by the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders which include intellectual disability,communication disorders,autism spectrum disorder,attention-deficit/hyperactivity disorder,specific learning disorder(SLD),and motor disorders.SLD is present in many students,who exhibit significant difficulties in the acquisition of reading,written expression,and mathematics,mostly due to problems with executive functions(EF).The present study is a review of the current situation of neurodevelopmental disorders and SLD focusing on the benefits of the response to intervention model(RtI),which allows the combination of evaluation and intervention processes.It also addresses the key role of EF.The importance of adapting RtI to new possibilities such as the use of virtual reality is discussed and a theoretical framework for carrying that out is provided.
基金supported by grants from Fritz Thyssen Stiftung,Brain Boost Innovation Center by Sagol School of Neuroscience at TAU,and SPARK Tel Avivsupported by the Eshkol Fellowship from The Ministry of Science and Technologythe recipient of The Alon Fellowship for outstanding young researchers awarded by the Israeli Council for Higher Education。
文摘Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes,affecting individuals worldwide.While the subject has been heavily researched,current treatment options relate mostly to alleviating symptoms,rather than targeting the altered genome itself.In this review,we address the neurogenetic basis of neurodevelopmental disorders,genetic tools that are enabling precision research of these disorders in animal models,and postnatal gene-therapy approaches for neurodevelopmental disorders derived from preclinical studies in the laboratory.
基金supported by the Guangdong Key Project in“Development of new tools for diagnosis and treatment of Autism”(2018B030335001 to Z.Sun)and“Early diagnosis and treatment of autism spectrum disorders”(202007030002 to Z.Sun)the National Natural Science Foundation of China(32070590 to Y.Wang)+5 种基金the National Natural Science Foundation of China(81730036 and81525007 to K.Xia)Science and Technology Major Project of Hunan Provincial Science and Technology Department(2018SK1030 to K.Xia)the National Natural Science Foundation of China(81801133 to J.Li)the Young Elite Scientist Sponsorship Program by CAST(2018QNRC001 to J.Li)the Innovation-Driven Project of Central South University(20180033040004 to J.Li)Natural Science Foundation of Hunan Province for outstanding Young Scholars(2020JJ3059 to J.Li)。
文摘Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 NDD-related genes in 3,195 Chinese probands with neurodevelopmental phenotypes and identify 2,522 putative functional mutations consisting of 137 de novo mutations(DNMs)in 86 genes and 2,385 rare inherited mutations(RIMs)with 22 X-linked hemizygotes in 13 genes,2 homozygous mutations in 2 genes and 23 compound heterozygous mutations in 10 genes.Furthermore,the DNMs of16,807 probands with NDDs are retrieved from public datasets and combine in an integrated analysis with the mutation data of our Chinese NDD probands by taking 3,582 in-house controls of Chinese origin as background.We prioritize 26 novel candidate genes.Notably,six of these genes d ITSN1,UBR3,CADM1,RYR3,FLNA,and PLXNA3 d preferably contribute to autism spectrum disorders(ASDs),as demonstrated by high co-expression and/or interaction with ASD genes confirmed via rescue experiments in a mouse model.Importantly,these genes are differentially expressed in the ASD cortex in a significant manner and involved in ASD-associated networks.Together,our study expands the genetic spectrum of Chinese NDDs,further facilitating both basic and translational research.
文摘Biological entities are involved in complicated and complex connections;hence,discovering biological information using network biology ideas is critical.In the past few years,network biology has emerged as an integrative and systems-level approach for understanding and interpreting these complex interactions.Biological network analysis is one method for reducing enormous data sets to clinically useful knowledge for disease diagnosis,prognosis,and treatment.The network of biological entities can help us predict drug targets for several diseases.The drug targets identified through the systems biology approach help in targeting the essential biological pathways that contribute to the progression and development of the disease.The novel strategical approach of system biologyassisted pharmacology coupled with computer-aided drug discovery(CADD)can help drugs fight multifactorial diseases efficiently.In the present review,we have summarized the role and application of network biology for not only unfolding the mechanism of complex neurodevelopmental disorders but also identifying important drug targets for diseases like ADHD,Autism,Epilepsy,and Intellectual Disability.Systems biology has emerged as a promising approach to identifying drug targets and aiming for targeted drug discovery for the precise treatment of neurodevelopmental disorders.
基金funded by the National Natural Science Foundation of China(No.82160620)the Natural Science Foundation of Guangxi Province,China(No.2023GXNSFAA026036)the Guangxi College Students Innovation and Entrepreneurship Training Program(China)(No.S202310601164).
文摘Kelch-like family member 17(KLHL17)is predominantly expressed in the brain and plays a crucial role in neuronal development and function,deletions and/or mutations in KLHL17 have been linked to neurodevelopmental disorders in humans,e.g.,intellectual disability,autism spectrum disorder,and infantile spasms,but the etiology and pathogenesis remain largely enigmatic.1,2 As a member of the family of the Kelch proteins,KLHL17 contains an N-terminal BTB/POZ domain followed by a BACK domain and four to six tandem Kelch motifs at the C-terminal region(Fig.S1A).1,3 Previously,we identified a novel de novo variant in KLHL17(c.701C>T;p.P234L)in a cohort of 225 Chinese children with developmental delay/intellectual disability based on whole-exome sequencing(1/225),the mutation located in the BACK domain,a very high conversed region(Fig.S1B),and the affected boy presented with developmental delay,intellectual disability,hypotonia,and abnormal brainstem auditory evoked potential signal.4 The finding may offer a new clue to investigate the molecular pathogenesis of KLHL17 gene in neurodevelopmental disorders.
基金supported by the National Key Research and Development Program of China(2022YFC2703900)the CAMS Innovation Fund for Medical Sciences(2021-I2M-1018)+1 种基金the National Natural Science Foundation of China(82394420 and 82394423)the Theranostics and Translational Research Facility of National Infrastructures for Translational Medicine,Institute of Clinical Medicine,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College for the support。
文摘Dear Editor,Neurodevelopmental disorders(NDD)are a group of diseases with high phenotypic heterogeneity characterized by inability in cognition,communication,psychological skills,and motor development.The common types of NDDs include autism spectrum disorder(ASD),attention-deficit/hyperactivity disorder(ADHD),epilepsy,schizophrenia,etc.(Parenti et al.,2020).
基金supported,in part,by grants from the National Natural Science Foundation of China(82201314)by the Fundamental Research Funds for the Central Universities starting fund(BMU2022RCZX038)to T.W.
文摘Neurodevelopmental disorders(NDDs)are a group of highly heterogeneous diseases that affect children’s social,cognitive,and emotional functioning.The etiology is complicated with genetic factors playing an important role.During the past decade,large-scale whole exome sequencing(WES)and whole genome sequencing(WGS)have vastly advanced the genetic findings of NDDs.Various forms of variants have been reported to contribute to NDDs,such as de novo mutations(DNMs),copy number variations(CNVs),rare inherited variants(RIVs),and common variation.By far,over 200 high-risk NDD genes have been identified,which are involved in biological processes including synaptic function,transcriptional and epigenetic regulation.In addition,monogenic,oligogenic,polygenetic,and omnigenic models have been proposed to explain the genetic architecture of NDDs.However,the majority of NDD patients still do not have a definitive genetic diagnosis.In the future,more types of risk factors,as well as noncoding variants,are await to be identified,and including their interplay mechanisms are key to resolving the etiology and heterogeneity of NDDs.
基金This work was supported by National key research and development program,2022YFA1303900National Natural Science Foundation of China(NSFC)grant no.82172288.
文摘The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis,regulating various physiological processes.In recent years,the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated.The gut microbiota is commonly considered to regulate neurodevelopment through three pathways,the immune pathway,the neuronal pathway,and the endocrine/systemic pathway,with overlaps and crosstalks in between.Accumulating studies have identified the role of the microbiota-gut-brain axis in neurodevelopmental disorders including autism spectrum disorder,attention deficit hyperactivity disorder,and Rett Syndrome.Numerous researchers have examined the physiological and pathophysiological mechanisms influenced by the gut microbiota in neurodevelopmental disorders(NDDs).This review aims to provide a comprehensive overview of advancements in research pertaining to the microbiota-gut-brain axis in NDDs.Furthermore,we analyzed both the current state of research progress and discuss future perspectives in this field.
基金the NEVET Nanotechnology Grant of the Russell Berrie Nanotechnology Institute(RBNI)at Technion—Israel Institute of Technology(Israel)the Tamara and Harry Handelsman Academic Chair(Israel)for financial support。
文摘Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.
基金supported by a grant from Zhejiang Province Public Welfare Technology Application Research Project(No.LQ19C090007)the start funds of the Children's Hospital Zhejiang University School of MedicineERA-NET SynPathy from Neuron Network of European Funding for Neuroscience Research.
文摘Background Formation of protein complexes across synapses is a critical process in neurodevelopment,having direct implications on brain function and animal behavior.Here,we present the understanding,importance,and potential impact of a newly found regulator of such a key interaction.Data sources A systematic search of the literature was conducted on PubMed(Medline),Embase,and Central-Cochrane Database.Results Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins(MDGAs)were recently discovered to regulate synaptic development and transmission via suppression of neurexins-neuroligins transsynaptic complex formation.MDGAs also regulate axonal migration and outgrowth.In the context of their physiological role,we begin to consider the potential links to the etiology of certain neurodevelopmental disorders.We present the gene expression and protein structure of MDGAs and discuss recent progress in our understanding of the neurobiological role of MDGAs to explore its potential as a therapeutic target.Conclusion MDGAs play a key role in neuron migration,axon guidance and synapse development,as well as in regulating brain excitation and inhibition balance.
文摘‘Neurodevelopmental disorders’comprise a group of congenital or acquired longterm conditions that are attributed to disturbance of the brain and or neuromuscular system and create functional limitations,including autism spectrum disorder,attention deficit/hyperactivity disorder,tic disorder/Tourette’s syndrome,developmental language disorders and intellectual disability.Cerebral palsy and epilepsy are often associated with these conditions within the broader framework of paediatric neurodisability.Co-occurrence with each other and with other mental health disorders including anxiety and mood disorders and behavioural disturbance is often the norm.Together these are referred to as neurodevelopmental,emotional,behavioural,and intellectual disorders(NDEBIDs)in this paper.Varying prevalence rates for NDEBID have been reported in developed countries,up to 15%,based on varying methodologies and definitions.NDEBIDs are commonly managed by either child health paediatricians or child/adolescent mental health(CAMH)professionals,working within multidisciplinary teams alongside social care,education,allied healthcare practitioners and voluntary sector.Fragmented services are common problems for children and young people with multi-morbidity,and often complicated by subthreshold diagnoses.Despite repeated reviews,limited consensus among clinicians about classification of the various NDEBIDs may hamper service improvement based upon research.The recently developed“Mental,Behavioural and Neurodevelopmental disorder”chapter of the International Classification of Diseases-11 offers a way forward.In this narrative review we search the extant literature and discussed a brief overview of the aetiology and prevalence of NDEBID,enumerate common problems associated with current classification systems and provide recommendations for a more integrated approach to the nosology and clinical care of these related conditions.
