Jul 2026· Current Neuropharmacology· Vol 24· 0 citations
Medicine
TL;DR
The evidence suggests that myelin-related pathways represent a common point of vulnerability across disorders and may offer a potential target for intervention, integrating findings from both animal models and human research.
Abstract
Myelination is a fundamental neurobiological process that enables rapid and efficient neural signal transmission, playing a key role in shaping brain connectivity and function-particularly during early development. Given the high energetic cost and tight developmental timing of myelination, disruptions in myelin formation or maintenance can increase vulnerability to genetic and environmental factors during critical periods. As such, impaired myelination and oligodendrocyte dysfunction may contribute to the pathogenesis of various neurodevelopmental disorders (NDDs). This review synthesizes current knowledge on the role of myelin-related changes in the pathophysiology of NDDs-including Autism Spectrum Disorder (ASD), Attention-Deficit/ Hyperactivity Disorder (ADHD), Fetal Alcohol Spectrum Disorders (FASD), intellectual developmental disorders, and communication, motor, and specific learning disorders-integrating findings from both animal models and human research. Taken together, the evidence suggests that myelin-related pathways represent a common point of vulnerability across disorders and may offer a potential target for intervention.
Alcohol Use Disorder (AUD) is a leading risk factor for negative health consequences associated with disruptions in neural functions. While alcohol-induced neuronal adaptations have remained in the spotlight for researchers investigating AUD, growing evidence highlights glial cell populations and their contributions to AUD pathology. This review explores the role of oligodendrocytes (OLs) and their progenitors (OPCs) in alcohol-induced alterations of white matter (WM), myelin structure, composition, and integrity. Human neuroimaging studies reveal reductions in WM volume and microstructural integrity, accompanied by molecular evidence of impaired myelin architecture and lipid composition in postmortem brains. Preclinical models provide causal evidence linking alcohol to dose-, length of exposure-, and brain-region-dependent dysregulation of OLs at transcriptional, structural, and metabolic levels. Investigations of the underlying mechanisms implicate oxidative stress, neuroinflammation, transcriptional changes, epigenetic modifications, and lipid dysregulation as key pathways through which alcohol disrupts OLs. Because OLs are essential for proper myelination, neural function, and brain connectivity, alcohol-induced changes in these processes likely contribute to the cognitive, learning, and emotional deficits associated with AUD. Investigations into prenatal and adolescent alcohol exposure reveal impairments in OL maturation and myelination that produce long-lasting deficits which persist into adulthood. Together, these findings support alcohol-induced OL dysregulation and circuit disruption as drivers in AUD pathology. Understanding how alcohol impacts OLs and OPCs at both molecular and developmental levels is critical for identifying novel therapeutic targets aimed at ameliorating disruptions to WM integrity, diagnosing AUD, and improving outcomes for individuals impacted by AUD.
Hazen Westover, Esther Melamed, Jennifer T. Wolstenholme et al.· Physiology and Behavior· 0 citations
INTRODUCTION
Oligodendrocytes (OLs) synthesize myelin, a substance that plays a significant role in ensuring proper functioning of the Central Nervous System (CNS). Myelin abnormalities are involved in disease pathogenesis in AD, MS, and ALS. In contrast, MS involves autoimmune reactions directed against myelin. On the other hand, AD and ALS are characterized by neurodegeneration. This article seeks to give a critical discussion on myelin and OL dysfunction in these diseases, among others.
METHODS
A narrative literature search was carried out in various databases including Scopus, Google Scholar, Web of Science, and PubMed, focusing on papers relating to myelination, remyelination, and OLs, particularly those addressing signaling pathways and treatment strategies.
RESULTS
MS is an autoimmune disease characterized by inflammation that causes demyelination and OL dysfunction. Oxidative stress and mitochondrial dysfunction play roles in the pathogenesis of ALS, whereas AD is a result of disrupted neuronal supportive functions and myelin damage. Important signaling pathways involved in OL formation and myelin repair include the Wnt/β-catenin, AKT/mTOR, and ERK/MAPK pathways. Drugs like edaravone, ocrelizumab, and siponimod have been identified for promoting myelin repair.
DISCUSSION
The relationship between abnormal oligodendrocyte function, demyelination, and specific disease-related pathological processes demonstrates that although there is a similarity among MS, AD, and ALS, each condition possesses its own unique molecular foundation. One potential treatment approach would be targeting shared signaling pathways relevant to myelination and remyelination. Nonetheless, disease variability and specific pathogenic characteristics demand a targeted therapy approach.
CONCLUSION
Myelin integrity and oligodendrocyte function are central to the progression of demyelinating and neurodegenerative diseases. Targeting molecular pathways involved in myelination offers significant potential for improving disease outcomes and developing advanced therapeutic strategies.
Shivang Shukla, Vivek Srivastava, H. Gaur et al.· CNS and Neurological Disorde...· 0 citations
The study provides an integrated framework linking genetic variation to molecular dysfunction and clinical outcomes, offering valuable insights for future research and therapeutic development in pediatric neurology.
Varada Vidya Rani, Suryanarayana Reddy Kovvuri, D. Arya· Genetics and Molecular Resea...· 0 citations
Attention deficit hyperactivity disorder (ADHD) is hypothesized to be associated with delayed brain maturation rather than atypical brain development. While this developmental delay hypothesis has gained widespread recognition, research progress has stagnated, and the field lacks a consolidated overview of existing findings and challenges. This narrative review integrates multi-dimensional findings across behavioral manifestations, electroencephalography (EEG), structural,diffusion, and functional magnetic resonance imaging (MRI), and genetics, supporting a regionally specific and multi-trajectory heterogeneous delay model. Based on a critical discussion of the literature and recent advancements, four critical unresolved challenges are identified: (1) incomplete explanatory power of delay phenomena; (2) whether temporal delays lead to reduced peak amplitudes in developmental trajectories; (3) whether delayed trajectories can achieve developmental "catch-up" prior to brain maturation; and (4) heterogeneity in delayed developmental pathways. To address these challenges, we propose four strategies: (1) establishing longitudinal high-density tracking cohorts; (2) constructing multimodal brain-age prediction models; (3) identifying neurodevelopmental delay subtypes through heterogeneity modeling; and (4) quantifying ADHD-related developmental delays via disease progression modeling. These approaches aim to lay a foundation for precise diagnosis, treatment, and early intervention in ADHD. This review integrates existing evidence on the developmental delay hypothesis to help focus future efforts, while highlighting current challenges and potential solutions to inspire innovative directions for research into the neurodevelopmental mechanisms underlying ADHD.
Leilei Ma, Yujie Cao, Ningyu Liu et al.· Biological Psychiatry: Cogni...· 0 citations
Schizophrenia is a chronic and heterogeneous neuropsychiatric condition that affects approximately one percent of the global population and is associated with substantial impairments in perception, cognition, emotional regulation, and social functioning. The disorder typically manifests during late adolescence or early adulthood and arises from a complex interaction between genetic susceptibility and environmental influences acting during critical stages of brain development. Clinically, schizophrenia is characterized by three major symptom clusters: positive symptoms, including hallucinations, delusions, and disorganized thinking; negative symptoms, such as reduced motivation, emotional blunting, social withdrawal, and diminished pleasure; and cognitive deficits involving attention, memory, learning, and executive processing. Traditional dopamine-centered theories primarily explain the emergence of positive symptoms but fail to adequately account for persistent negative and cognitive impairments. Contemporary research highlights the involvement of glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor hypofunction, altered serotonergic signaling, and disrupted cortico–striatal–thalamic connectivity. Neuroimaging studies further demonstrate widespread structural and functional brain abnormalities, supporting a neurodevelopmental basis for the disorder. Increasing evidence also implicates neuroinflammatory processes, immune imbalance, and oxidative stress in the progression of neuronal dysfunction and white matter damage. Although currently available antipsychotic medications effectively alleviate positive symptoms in many patients, their clinical benefit is limited by adverse effects and insufficient efficacy against negative and cognitive domains. These limitations emphasize the necessity for safer and more comprehensive therapeutic strategies. This review summarizes current understanding of the clinical features, etiological factors, biological mechanisms, and pharmacological management of schizophrenia, while outlining emerging therapeutic targets that may guide future research and drug development.
Vaishnavi S. Solav, A. Wankhade, V. Paithankar et al.· Research Journal of Pharmaco...· 0 citations
Vitamin D deficiency is highly prevalent in children worldwide but has long been regarded only as a risk factor for bone health. Emerging evidence indicates that vitamin D profoundly influences child brain development by regulating neuroimmune responses and synaptic plasticity, forming a “neuroimmune–synaptic plasticity axis.” Deficiency is significantly associated with the risk of multiple pediatric neurological disorders, including autism spectrum disorder (ASD), epilepsy, and attention-deficit / hyperactivity disorder (ADHD). This axis exerts irreversible regulatory effects during critical developmental windows from gestation to the preschool period, representing a core causal pathway linking vitamin D deficiency to neurodevelopmental disorders. However, the clinical benefits of vitamin D supplementation are highly heterogeneous, necessitating a move beyond the “one-size-fits-all” paradigm. This review systematically integrates causal mechanisms, molecular pathways, disease-specific associations, and clinical evidence, proposing the “neuroimmune–synaptic plasticity axis” as a central hypothesis. We critically analyze the mechanisms of vitamin D during key neurodevelopmental periods and evaluate sources of heterogeneity in existing clinical trials, including dosage, timing, VDR genotype, and co-nutrients. Finally, we propose a research roadmap for individualized supplementation strategies based on developmental stage, biomarkers, and VDR genotype, aiming to transition vitamin D use from empirical to precision intervention.
C. Xie, Ping Xiang, Xinyun Ye et al.· Frontiers in Aging Neuroscie...· 0 citations