ASN Neuro[JOURNAL]
Sun
200 papers
Border-Associated Macrophages in CNS Health and Disease: A Comprehensive Review of Ontogeny, Heterogeneity, and Functional Plasticity at Neural Interfaces.
Liu X, Li M, Wei Z … +2 more , Shang T, Zou W
ASN Neuro · 2026 Jun · PMID 42397694 · Publisher ↗
Border-associated macrophages (BAMs) represent a specialized population of tissue-resident immune cells strategically positioned at the critical interfaces between the central nervous system (CNS) and peripheral circulat...
Border-associated macrophages (BAMs) represent a specialized population of tissue-resident immune cells strategically positioned at the critical interfaces between the central nervous system (CNS) and peripheral circulation, including the meninges, choroid plexus, and perivascular spaces. As frontline sentinels of the neuroimmune system, BAMs perform essential functions in immune surveillance, barrier integrity maintenance, and homeostatic regulation, yet their unique biology and disease-associated roles remain incompletely characterized compared to parenchymal microglia. This review aims to synthesize current knowledge on BAM ontogenetic origins, compartment-specific heterogeneity, transcriptional programs, and functional outputs in both health and neurological disorders. We conducted a comprehensive literature analysis integrating findings from lineage tracing studies, single-cell RNA sequencing, spatial transcriptomics, and functional interrogation in animal models of disease. The results reveal that BAMs exhibit remarkable cellular diversity shaped by distinct ontogenetic origins-primarily yolk sac-derived erythro-myeloid progenitors with variable contributions from fetal liver and postnatal monocytes depending on anatomical compartment. Compartment-specific marker combinations (CD206, LYVE1, CD163, MHCII) define functionally distinct subsets, and core transcriptional regulators including PU.1 and IRF8 maintain BAM identity while CSF-1/IL-34-CSF1R signaling governs survival and renewal. In neurological disorders including ischemic stroke, Alzheimer's disease, multiple sclerosis, and brain tumors, BAMs display pronounced double-edged roles, transitioning from protective homeostatic guardians to pathogenic drivers depending on disease stage and microenvironmental context. This comprehensive analysis establishes a unified framework for understanding BAM biology and identifies critical opportunities for developing subset-specific therapeutic strategies targeting these interface macrophages in neurological diseases.
Role of E3 Ubiquitin Ligases in Oligodendrocyte Health and Disease.
Mabb AM, Pyaram DN, Samanta J
ASN Neuro · 2026 · PMID 42384823 · Publisher ↗
Protein ubiquitination is a type of posttranslational modification that occurs in all cells to regulate numerous biological processes. Ubiquitination of proteins is carried out by an enzymatic cascade where E3 ubiquitin...
Protein ubiquitination is a type of posttranslational modification that occurs in all cells to regulate numerous biological processes. Ubiquitination of proteins is carried out by an enzymatic cascade where E3 ubiquitin ligases facilitate the final step in the transfer of ubiquitin to substrates. This review focuses on the role of E3 ubiquitin ligases in the regulation of oligodendrocytes, a glial cell type in the central nervous system that is critical for axon myelination and overall neuronal health. Here we focus on how protein ubiquitination dominantly driven by E3 ubiquitin ligase enzymes alters the development, maintenance, and disease pathogenesis in oligodendrocytes.
Progress in Research on the Mechanisms and Therapeutic Targets of Ferroptosis in Peripheral Nerve Injury and Repair.
Ruan J, He XK, Zhang SO … +3 more , Teng XF, Hu Y, Chen H
ASN Neuro · 2026 · PMID 42200802 · Full text
Repair after peripheral nerve injury (PNI) faces major obstacles due to microenvironmental imbalance and neuronal loss. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, has emerged as a key patholo...
Repair after peripheral nerve injury (PNI) faces major obstacles due to microenvironmental imbalance and neuronal loss. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, has emerged as a key pathological event in PNI, linking oxidative stress, mitochondrial dysfunction, and inflammation to regenerative failure. Targeting ferroptosis protects vital cells-such as Schwann cells and neurons-and ameliorates the regenerative niche, offering a promising therapeutic strategy. This review elucidates the mechanisms of ferroptosis in PNI, detailing its roles in Schwann cells, dorsal root ganglion neurons, and macrophages via core pathways including Nrf2/HO-1/GPX4 and ACSL4. We further evaluate current intervention strategies and their therapeutic efficacy. This synthesis provides novel insights into PNI pathology and guides the development of innovative treatments.
Polyglutamine-Expanded Ataxin-3 Accelerates CFTR Degradation Through K63-Linked Ubiquitination to Exacerbate Microglial Inflammation.
Wang Z, Fan X, Bai B … +9 more , Song M, Shi Y, Zhao Y, Xie P, Shi T, He C, Hu Y, Wu Q, Hou X
ASN Neuro · 2026 · PMID 42189036 · Full text
The deubiquitinase Ataxin-3 causes spinocerebellar ataxia type 3 (SCA3) upon polyglutamine (polyQ) expansion. While expressed in the nervous system, the function of the cystic fibrosis transmembrane conductance regulator...
The deubiquitinase Ataxin-3 causes spinocerebellar ataxia type 3 (SCA3) upon polyglutamine (polyQ) expansion. While expressed in the nervous system, the function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel therein remains unclear, as does its potential regulation by Ataxin-3. This study reveals that Ataxin-3 interacts with and promotes CFTR degradation in human microglia by its K63-linked polyubiquitination, thereby shortening CFTR's half-life. Paradoxically, K63-linked polyubiquitin chains also promote the degradation of Ataxin-3 itself, suggesting a complex feedback mechanism. The pathogenic Ataxin-3Q80 mutant exerts a stronger effect than the wild-type protein. Consequently, this Ataxin-3-CFTR axis drives microglial polarization toward a pro-inflammatory phenotype and amplifies neuroinflammation. We thus identify a novel "Ataxin-3-K63 ubiquitin chain-CFTR" pathway that controls microglial activation, offering new mechanistic insight and therapeutic targets for SCA3. MJDM: achado-Joseph disease; SCA3: spinocerebellar ataxia type 3; PolyQ: polyglutamine; CNS: central nervous system; CFTR: cystic fibrosis transmembrane conductance regulator; CF: cystic fibrosis; UIMs: ubiquitin-interacting motifs; MEM: Minimum Essential Medium; FBS: fetal bovine serum; P/S: penicillin/streptomycin; siRNA: small interfering RNA; BSA: bovine serum albumin; Co-IP: Co-immunoprecipitation; LPS: lipopolysaccharide; WT-CFTR: wild-type CFTR; CHX: Cycloheximide; 3-MA: 3-Methyladenine; IF: Immunofluorescence; IB: immunoblot; Ub: ubiquitin.
Exposure to Frontline Antiretroviral Dolutegravir Disrupts Oligodendrocyte Development Across Differentiation Stages.
Jeffries MA, Putatunda R, Cruz-Berríos M … +4 more , Romer MA, Singhal A, Jordan-Sciutto KL, Grinspan JB
ASN Neuro · 2026 · PMID 41904696 · Full text
The use of antiretroviral (ART) treatment during pregnancy has dramatically reduced rates of perinatally-acquired human immunodeficiency virus 1 (HIV-1) infection to <1% in the United States. Despite this success, we hav...
The use of antiretroviral (ART) treatment during pregnancy has dramatically reduced rates of perinatally-acquired human immunodeficiency virus 1 (HIV-1) infection to <1% in the United States. Despite this success, we have limited knowledge of how ART drugs that cross the placental barrier affect fetal development, particularly in the central nervous system (CNS). During gestation, large populations of oligodendroglia are produced that are responsible for critical postnatal CNS myelination enabling appropriate neurological function. Previous studies have shown that antiretrovirals impair oligodendrocyte (OL) differentiation leading us to hypothesize that OL maturation might be inhibited by exposure to a frontline ART drug cocktail (Triumeq®) prescribed during pregnancy containing dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC). In this study, we demonstrated that exposing primary rat oligodendrocyte precursor cells (OPCs) and OLs to the Triumeq drug combination decreased OL maturation and myelin protein production in a concentration-dependent manner, and that DTG was solely responsible. Regardless of the timing of exposure during OL development, a high concentration of DTG inhibited OL maturation. Bulk RNA sequencing revealed transcriptional changes after DTG exposure related to a variety of cellular mechanisms, including cellular responses to stress pathways, amino acid starvation, and mitochondrial dysfunction. Although we found that DTG robustly activated the integrated stress response (ISR), attempted rescue experiments showed that DTG primarily inhibits OL maturation independently of the ISR. Collectively, our novel data on DTG underscore the necessity of investigating how ART drugs that are administered during pregnancy and cross the placental barrier can affect fetal CNS development.
Membrane Molecular Species Remodeling as a Signature of ω-3 Fatty Acid Action in Cultured Neural Cells.
Nicholas KR, Taborda Ribas H, Browne KD … +6 more , Purpura KR, Xu P, Mani A, Krizman EN, Mesaros C, Cullen DK
ASN Neuro · 2026 · PMID 41865307 · Full text
Omega-3 polyunsaturated fatty acids (ω3 PUFAs) are critical structural components of neuronal membranes, yet the molecular specificity of their incorporation within neural cells remains incompletely defined. We integrate...
Omega-3 polyunsaturated fatty acids (ω3 PUFAs) are critical structural components of neuronal membranes, yet the molecular specificity of their incorporation within neural cells remains incompletely defined. We integrated untargeted and targeted lipidomics with lipid ontology analysis and coarse-grained membrane simulations to characterize remodeling in primary rat cortical neurons and neuron-astrocyte co-cultures following supplementation with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), or docosapentaenoic acid (DPA). Each ω3 PUFA produced a distinct lipidomic signature. DHA showed the most consistent incorporation, selectively enriching phosphatidylethanolamine (PE) species-particularly PE(18:0/22:6) and PE(18:1/22:6)-associated with membrane curvature and organelle organization. Ontology analysis linked DHA supplementation to intrinsic curvature-related membrane features, and membrane simulations demonstrated enhanced collective bilayer bending without substantial changes in overall membrane thickness. EPA preferentially increased EPA-containing PE species without elevating DHA levels, whereas DPA effects were variable and culture-dependent, indicating selective metabolic handling of individual ω3 species. Differences between neurons and neuron-astrocyte co-cultures underscore the importance of cellular context in ω3-driven remodeling. By resolving ω3 incorporation at molecular species resolution and linking compositional changes to predicted membrane behavior, this study provides a structural framework for understanding how dietary ω3 fatty acids may influence neuronal membrane organization and cellular resilience.
Reboxetine Treatment Reduces Hippocampal Gliosis in the P301S Tauopathy Mouse Model.
Gutiérrez IL, Yanes-Castilla C, MacDowell KS … +5 more , Caso JR, García-Bueno B, Ulecia-Morón C, Leza JC, Madrigal JLM
ASN Neuro · 2026 · PMID 41722088 · Full text
The loss of brain noradrenergic neurons is one of the earliest alterations observed in Alzheimer's disease and other neurodegenerative pathologies. The consequent reduction of brain noradrenaline levels facilitates the p...
The loss of brain noradrenergic neurons is one of the earliest alterations observed in Alzheimer's disease and other neurodegenerative pathologies. The consequent reduction of brain noradrenaline levels facilitates the progression of neuroinflammatory processes that can be fatal for neurons and other brain cells. For this reason, compensating for noradrenaline deficit through different means constitutes an interesting therapeutic strategy. Drugs that inhibit the reuptake of noradrenaline are used to elevate the extracellular concentrations of this neurotransmitter and potentiate this way its effects. These drugs are approved for the treatment of depression or attention deficit hyperactivity disorder, among other indications, but their repurposing and use in Alzheimer's disease could be of interest given the beneficial effects observed for noradrenaline in numerous studies. Based on this, we previously showed the beneficial effects of reboxetine, a noradrenaline reuptake inhibitor, on 5xFAD mice that accumulate amyloid beta in their brains and reproduce some of the typical alterations of Alzheimer's disease. In this study we have analyzed the effects of reboxetine on P301S mice, a different model of Alzheimer's disease based on the expression of mutant forms of human microtubule-associated protein tau. We observed that the administration of reboxetine with osmotic pumps for 28 days to 9-month-old mice reduced the accumulation and activation of microglia and astrocytes in different areas of the hippocampus. These findings indicate that reboxetine treatment prevents the neuroinflammatory response known to cause brain damage in Alzheimer's disease even when the treatment is initiated at an advanced stage of the disease.
Targeting NLRP3 Inflammasome and Metabolic Dysregulation by Electroacupuncture: A Novel Therapeutic Strategy for Methamphetamine Withdrawal-Induced Depression.
Zhang X, Zhao XR, You CL … +4 more , Zhang F, Zhu HY, Gu T, Li J
ASN Neuro · 2026 · PMID 41686703 · Full text
This study demonstrates that electroacupuncture (EA) produces robust antidepressant effects in a rat model of methamphetamine (METH) withdrawal. Behavioral tests showed that EA applied at GV20, PC6, and HT7 significantly...
This study demonstrates that electroacupuncture (EA) produces robust antidepressant effects in a rat model of methamphetamine (METH) withdrawal. Behavioral tests showed that EA applied at GV20, PC6, and HT7 significantly reduced immobility in the forced swim test and enhanced exploratory activity in the open field test. Mechanistically, EA repaired blood-brain barrier (BBB) disruption, as shown by reduced hippocampal water content, decreased Evans Blue leakage, and restored expression of tight-junction proteins (Occludin, Claudin-5, ZO-1). EA also inhibited neuronal apoptosis, suppressed microglial activation, and lowered pro-inflammatory cytokines IL-6 and TNF-α. Multi-omics analyses revealed that EA reversed METH-induced alterations in 32 differentially expressed genes related to the NLRP3 inflammasome pathway (Nlrp3, Pycard, Il1b) and BBB function, while metabolomic profiling identified 13 key metabolites involved in glutamate metabolism, TCA cycle, and tryptophan pathways. Crucially, the therapeutic benefits of EA were abolished by intracerebroventricular administration of the NLRP3 activator nigericin, confirming the essential role of NLRP3 inflammasome inhibition in EA's mechanism of action. In summary, EA represents a promising non-pharmacological approach for treating METH withdrawal-induced depression by coordinating BBB protection, suppression of neuroinflammation, and metabolic network regulation.
Galectin-3 in the Lateral Ventricle Regulates Immune Functions.
Soares LC, Bernhardova H, Szele FG
ASN Neuro · 2026 · PMID 41655024 · Full text
Galectin-3 (Gal-3) is a protein expressed by glia that belongs to an ancient family. Gal-3 recognises molecular patterns on pathogens due to the high degree of its binding specificity with carbohydrate recognition domain...
Galectin-3 (Gal-3) is a protein expressed by glia that belongs to an ancient family. Gal-3 recognises molecular patterns on pathogens due to the high degree of its binding specificity with carbohydrate recognition domains. Thus, in sponges as well as other invertebrates, galectins are an important component of the primitive innate immune system. Whereas Gal-3's function in driving mammalian inflammation is well known, its function in warding off bacterial and viral infections is not well appreciated. One route of brain infection is via the cerebrospinal fluid brain interface (CSFBI) which is primarily composed of ependymal cells (EC). ECs express high levels of Gal-3, and their motile cilia are compromised in Gal-3 KOs. In this mini-review, we discuss fundamentally important potential roles of Gal-3 in pathogen recognition at the CSFBI and suggest avenues of further study.
GABA Receptor Activation in Müller Glia as a Molecular Switch for Controlling VEGF-A in the Retina.
Medina-Arellano AE, Albert-Garay JS, Tovar-Hernandez K … +2 more , Ruiz-Cruz M, Ochoa-de la Paz L
ASN Neuro · 2026 Jan · PMID 41621062 · Full text
GABA receptors are classically known for driving neuronal hyperpolarization and modulating synaptic transmission. In glial cells, however, GABA induces depolarization and triggers calcium-dependent signaling pathways. Mü...
GABA receptors are classically known for driving neuronal hyperpolarization and modulating synaptic transmission. In glial cells, however, GABA induces depolarization and triggers calcium-dependent signaling pathways. Müller glia, the principal retinal glial population, maintain retinal homeostasis and are the major source of neuroretinal VEGF-A, a key angiogenic factor in development and disease. Although GABA receptor (GABAR) activity has been proposed to influence retinal VEGF-A, it remains unclear whether this regulation occurs through Müller glial cells (MGC) and which mechanisms are involved. Here, we investigated how GABAR activation modulates VEGF-A in primary mouse MGC cultures. Cells were exposed to GABA and selective agonists or antagonists of GABA (muscimol, gabazine) and GABA receptors (baclofen, CGP55845). VEGF-A expression and secretion were analyzed by immunofluorescence, western blot, RT-qPCR, and ELISA. To assess Ca involvement, we used Ca-free Ringer-Krebs solution and the L-type channel blocker nimodipine, and examined MAPK signaling with the ERK1/2 inhibitor FR180204. Our findings show that GABA and muscimol increased VEGF-A fluorescence intensity after 48 hours while reducing VEGF-A secretion, without altering mRNA. Both effects were abolished by extracellular Ca removal or nimodipine, indicating a Ca-dependent mechanism. FR180204 also attenuated GABA- and GABA-mediated effects, implicating MAPK signaling. Short-term assays revealed that GABA rapidly elevates VEGF-A protein and secretion within ∼30 minutes. Together, these findings identify a Ca- and GABA-dependent pathway through which Müller glia regulate VEGF-A production and release, providing new insight into glial signaling and neurotransmitter-driven modulation of retinal angiogenic factors.
Disrupted Vitamin D Signaling and Metabolism in Neurodevelopmental and Neurodegenerative Disorders.
Khatibi N, MacDonald JL
ASN Neuro · 2026 Jan · PMID 41607305 · Full text
Vitamin D is a secosteroid hormone with myriad physiological functions, including pleiotropic effects in the central nervous system. Vitamin D deficiency has been linked to multiple neurodevelopmental and neurodegenerati...
Vitamin D is a secosteroid hormone with myriad physiological functions, including pleiotropic effects in the central nervous system. Vitamin D deficiency has been linked to multiple neurodevelopmental and neurodegenerative diseases, including Rett syndrome, epilepsy, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Over the past decades, vitamin D supplementation has been used as a preventative measure or a therapeutic intervention, often with inconsistent or variable responses. We discuss the known association between vitamin D deficiency and neurological disorder occurrence or progression for these disorders. Further, we assess the underlying causes for disruptions in vitamin D levels and the potential mechanisms of vitamin D-mediated improvements. We discuss disruptions in the vitamin D metabolism pathway, signaling, and/or feedback homeostasis that could underpin individual responses to vitamin D supplementation in these disorders. We further discuss the intersection between the vitamin D and cholesterol synthesis pathways and neuroinflammation, and the complex interactions that could contribute to the broad impact of vitamin D on neurological disorders.
Alpha-Synuclein Dynamics in Cerebral Ischemia.
Bordbar S, Molavizade S, Dehghani F … +3 more , Davoody S, Bahadori AR, Tafakhori A
ASN Neuro · 2026 Jan · PMID 41607299 · Full text
Cerebral ischemia is defined by insufficient blood supply to the brain and is a leading cause of mortality and neurological disability worldwide. Alpha-synuclein (α-Syn) is a protein associated with several neurodegenera...
Cerebral ischemia is defined by insufficient blood supply to the brain and is a leading cause of mortality and neurological disability worldwide. Alpha-synuclein (α-Syn) is a protein associated with several neurodegenerative disorders, including Parkinson's disease, and has also been linked to the pathophysiology of cerebral ischemia. This narrative review provides a detailed overview of the current understanding of α-Syn in cerebral ischemia. We examine its impact on neuroinflammation, synaptic dysfunction, oxidative stress, and neuronal cell death, as well as its potential protective roles. Additionally, we explore therapeutic strategies targeting α-Syn, including pharmacological agents, gene knockdown models, and RNA-based therapies. We also discuss α-Syn expression changes in animal and human studies and its potential as a diagnostic biomarker. By clarifying the complex interplay between α-Syn and cerebral ischemia, this review aims to deepen our understanding of ischemic brain injury mechanisms and support the development of novel treatment approaches.
Non-Synaptic Mechanism of Ocular Dominance Plasticity.
Foote MK, Huffman WC, Santos EN … +5 more , Lee PR, Jarnik M, Li W, Bonifacino JS, Fields RD
ASN Neuro · 2026 · PMID 41556652 · Full text
Classic experiments showing that monocular visual disruption alters synaptic connections to binocular neurons established the fundamental concept of synaptic plasticity. Synaptic inputs that are activated coincidently wi...
Classic experiments showing that monocular visual disruption alters synaptic connections to binocular neurons established the fundamental concept of synaptic plasticity. Synaptic inputs that are activated coincidently with postsynaptic action potential firing are strengthened, and inputs from cells firing before or after the postsynaptic action potential are weakened. An implicit assumption, however, is that the speed of impulse transmission is not altered by visual deprivation. If so, spike time arrival at binocular neurons would be affected, thereby inducing synaptic plasticity. This possibility is tested here in adult mice by monocular eyelid suture and monocular action potential inhibition in retinal axons. The results show that spike time arrival in visual cortex is altered by monocular visual disruption in association with morphological changes in myelin (nodes of Ranvier) on axons in optic nerve and optic tract. This non-synaptic mechanism of ocular dominance plasticity, mediated by myelin-forming cells, supplements and may drive synaptic plasticity.
Loss of Fatty Acid Oxidation by Neural Stem and Progenitor Cells Increases Proliferation but Does Not Improve Long-Term Neurogenesis After Mild Traumatic Brain Injury.
Allende Labastida J, Fernandez RF, Chu T … +5 more , Puleo N, Shishikura M, Wolfgang MJ, Scafidi J, Scafidi S
ASN Neuro · 2026 · PMID 41553195 · Full text
Neurogenesis in the dentate gyrus of the hippocampus is a conserved and highly regulated process throughout the lifespan. Hippocampal neural stem and progenitor cells (NSPCs) can either transition into an activated proli...
Neurogenesis in the dentate gyrus of the hippocampus is a conserved and highly regulated process throughout the lifespan. Hippocampal neural stem and progenitor cells (NSPCs) can either transition into an activated proliferative state or remain quiescent. Accumulating data suggests that mitochondrial fatty acid β-oxidation is important in maintaining NSPCs quiescence under normal physiological conditions; however, the contribution of this pathway in NSPCs following brain injury remains unknown. While severe traumatic brain injury (TBI) is characterized by increased NSPCs proliferation in the hippocampus, the extent of this proliferative response after mild TBI, the most prevalent form of TBI, has not been fully delineated. Using closed head injury as a model of mild TBI and a brain-specific knockout mouse of carnitine palmitoyltransferase 2 (CPT2; an obligate gene in mitochondrial fatty acid β-oxidation), we investigated the role of fatty acid oxidation in hippocampal NSPCs proliferation in naïve and injured male and female mice. Our results show that loss of CPT2 in the brain does not affect hippocampal proliferation in naïve mice. Furthermore, mild TBI upregulates proliferation at day 3 post-injury, and is further increased only in male CPT2-deficient mice. Despite the post-injury increase in hippocampal NSPCs proliferation in CPT2 mice, long-term neurogenesis remained unchanged. Together, these data provides a new insight into the metabolic regulation of NSPCs neurogenesis in the hippocampus following mild traumatic brain injury.
Loss of Thy1 in Cortico-Striatal Pathways Alters Response to Dopamine and Gabapentin.
Goletiani C, McEchron MD, Neely E … +1 more , Connor JR
ASN Neuro · 2026 Jan · PMID 41542890 · Full text
Thy1, a synaptic protein, may support synaptic junction adherence. Thus, we hypothesized that loss of Thy1 may alter synaptic transmission. Our focus on the Thy1 knockout (KO) mouse model stems from the loss of Thy1 expr...
Thy1, a synaptic protein, may support synaptic junction adherence. Thus, we hypothesized that loss of Thy1 may alter synaptic transmission. Our focus on the Thy1 knockout (KO) mouse model stems from the loss of Thy1 expression in individuals with Restless Legs Syndrome (RLS), a neurological disorder. This investigation aimed to determine: 1) if the absence of Thy1 affects synaptic function in the striatal region, 2) if the absence of Thy1 alters the synaptic response to dopamine and gabapentin, and 3) if the Thy1 loss can alter behavior modulated by the striatum. Network-level synaptic transmission was measured in corticostriatal slices from Thy1 KO and C57BL/6 control mice. , acoustic startle behavioral testing was used to measure startle reaction and prepulse inhibition in both groups. Raclopride, a D receptor antagonist, decreased population spike amplitude in control but not Thy1 KO slices. Quinpirole, a D receptor agonist, did not change spike amplitude in any group. Gabapentin, a Ca channel blocker, reduced population spike amplitude in Thy1 KO slices more than in controls. The behavioral acoustic startle response was diminished in Thy1 KO mice and attributed to enhanced prepulse inhibition. Loss of Thy1 alters striatal synaptic function, affecting dopaminergic modulation of corticostriatal neurotransmission and resulting in disruption of the startle response and prepulse inhibition.
Myelin Ratios: The Model Is in the Details.
Gow A
ASN Neuro · 2026 · PMID 41525149 · Full text
In contemporary myelin biology, there is a growing trend to prioritize faster, more convenient methodologies for evaluating white matter structure over quality of the analysis. This shift is often accompanied by less att...
In contemporary myelin biology, there is a growing trend to prioritize faster, more convenient methodologies for evaluating white matter structure over quality of the analysis. This shift is often accompanied by less attention to the mechanistic foundations of the methods in preclinical and clinical research. To address such worrisome trends, the current article assesses three approaches for estimating the myelin ratio from electron microscopy data, which is the gold standard approach to measure the impacts of neuropathology and treatment strategies on white matter integrity. Of the mathematical models examined, two are consistent with and equivalent to the linear relation defined by the axon versus fiber diameter plot (the principal data). The final model is the canonical almost universally accepted approach to measuring ratios. This model is demonstrated to be internally inconsistent and discordant with the axon versus fiber diameter relation and can lead to inaccurate conclusions about myelin integrity. Furthermore, the increasing interest in non-invasive neuroimaging approaches to measure ratios clinically in both physiologic and pathophysiologic studies necessitates calibration with electron microscopy-derived ratios. In this vein, mathematical models applicable to these methodologies are concordant; thus, magnetic resonance imaging holds significant promise for accurate determination of myelin integrity in patients. On the other hand, the metrics measurable by this voxel-based technology may preclude application to gray matter myelin and perhaps limit its use to linearly-organized white matter tracts.
MyeliMetric: A Python-Based Toolbox for Standardized G-Ratio Analysis of Axon-Myelin Integrity.
Ahmad I, Chowdhury FS, Boullerne AI … +2 more , Gow A, Feinstein DL
ASN Neuro · 2025 Dec · PMID 41431828 · Full text
The g-ratio, defined as the ratio of an axon's diameter to the total fiber diameter (axon plus myelin), is a key metric for assessing myelin integrity and axonal conduction velocity in both the central and peripheral ner...
The g-ratio, defined as the ratio of an axon's diameter to the total fiber diameter (axon plus myelin), is a key metric for assessing myelin integrity and axonal conduction velocity in both the central and peripheral nervous systems. Deviations from the physiological range often signal underlying pathology. Despite its diagnostic importance, there is currently no standardized, open-source tool for g-ratio analysis from post-segmented electron microscopy images. To address this gap, we developed MyeliMetric, a Python-based, user-friendly toolbox that streamlines g-ratio data preprocessing and integrates biologically informed validation, requiring minimal statistical expertise to operate without introducing common analytical errors. It is built on the principle that g-ratios exhibit relative consistency across varying axon diameters in healthy conditions. To rigorously assess this relationship, MyeliMetric implements a binning strategy that groups axons into biologically relevant diameter cohorts, enabling the detection of size-dependent deviations in g-ratio distributions. This approach addresses common limitations in conventional analyses, including insufficient sampling, pseudo-replication, and artifacts such as misleading regression slopes. Validation using both synthetic and published datasets from rodent models of demyelination demonstrated the tool's accuracy, reproducibility, and biological relevance. Synthetic data yielded expected outcomes, and in experimental models, MyeliMetric reliably detected reductions in myelin thickness through g-ratio shifts while minimizing artifacts, thereby providing biologically meaningful insights. It is available on GitHub: https://github.com/Intakhar-Ahmad/NeuroMyelin-G-Ratio-Analysis-Toolkit.
Glutamate-Dependent Dynamic DNA Methylation Regulates Excitatory Amino Acid Transporters in Bergmann Glia Cells: Role of AMPA Receptors.
Oyetayo BO, Subair T, Morales-Ramírez N … +9 more , Hernández-Kelly LC, Rodríguez-Campuzano AG, Ramírez-Martínez L, Nolasco-Hiniesta L, Calderón ES, Castelán F, López-Bayghen E, Felder-Schmittbuhl MP, Ortega A
ASN Neuro · 2026 · PMID 41416480 · Full text
Glial glutamate uptake through sodium-dependent excitatory amino acid transporters (EAATs) is essential for synaptic homeostasis. Epigenetic modifications and neurotransmitter receptor signaling influence glial function...
Glial glutamate uptake through sodium-dependent excitatory amino acid transporters (EAATs) is essential for synaptic homeostasis. Epigenetic modifications and neurotransmitter receptor signaling influence glial function although their interactive effects on glutamate transporter regulation remain poorly understood. To investigate how DNA methylation affects glutamate receptor-mediated regulation of its own removal, primary cultures from chick cerebellar Bergmann glial cells were used. Confluent monolayers were treated with a DNA methylation inhibitor. Glutamate transporter activity was assessed through radioactive uptake assays, while methylation levels within distinct regions of the promoter were analyzed by methylated DNA immunoprecipitation (MeDIP)-PCR. The role of cytoskeletal dynamics and calcium signaling was evaluated using pharmacological modulators. DNA hypomethylation sensitizes glial cells to glutamate receptors stimulation. Kinetic analyses show a statistically significant increase in the Michaelis-Menten constant V and a non-significant change in K, changes in reflect alterations in plasma membrane transporter numberinity. Pharmacological analysis revealed the involvement of the phosphatidyl inositol 3 kinase (PI3K), the Ca/calmodulin-dependent kinase II (CaMKII) and the mammalian target of rapamycin (mTOR) pathways, suggesting coordinated regulation of glutamate transport. Importantly, short-term activation of AMPA receptors induced hypomethylation of the promoter, suggesting the engagement of active demethylation pathways that sustain transporter expression during heightened excitatory activity. Together, these findings reveal a novel mechanism in which epigenetic flexibility and synaptic receptor activity converge to enhance glutamate uptake in glial cells. This synergy between DNA methylation and AMPA receptor signaling provide new insights into the mechanisms by which glial cells dynamically adapt to excitatory stress.
Crocetin as a Neuroprotective Agent: Targeting Western Diet-Induced Cognitive Dysfunction Through Antioxidant, Anti-Inflammatory and Gut-Brain Axis Modulation.
Babu Kondaveeti S, Gupta V, Dar AA … +7 more , Sheikh JA, Kumar D, Choudhary N, Tanwar R, Gupta S, Rani P, Vk A
ASN Neuro · 2026 · PMID 41416475 · Full text
Western diet-induced cognitive dysfunction is a rapidly emerging health challenge driven by excessive intake of high-fat, high-sugar, and ultra-processed foods. These dietary patterns promote neuroinflammation, oxidative...
Western diet-induced cognitive dysfunction is a rapidly emerging health challenge driven by excessive intake of high-fat, high-sugar, and ultra-processed foods. These dietary patterns promote neuroinflammation, oxidative stress, insulin resistance, gut dysbiosis, and blood-brain barrier (BBB) disruption, ultimately leading to synaptic dysfunction and cognitive decline. Crocetin, an apocarotenoid derived from saffron and , exhibits promising neuroprotective effects by scavenging reactive oxygen species, attenuating neuroinflammatory signaling, enhancing mitochondrial bioenergetics, and improving insulin sensitivity. It further upregulates brain-derived neurotrophic factor (BDNF), modulates PI3K/Akt signaling, and restores gut microbiota balance, thereby reinforcing the gut-brain axis and maintaining BBB integrity. This review further aims to critically assess these mechanistic links by distinguishing well-supported findings from speculative associations emphasizing discrepancies between preclinical and human evidence. Preclinical studies strongly support crocetin's role in ameliorating Western diet-induced neurodegeneration, while early clinical evidence highlights improvements in memory, executive function, and cerebral blood flow. However, limitations such as poor bioavailability, rapid metabolism, and limited large-scale human trials constrain its translation into clinical practice. Advanced formulations, including nanoparticles, liposomes, and prodrug derivatives, hold potential to overcome these challenges. This review critically evaluates the pathophysiological mechanisms of Western diet-induced cognitive decline, highlights the pharmacological actions of crocetin, and discusses its therapeutic prospects within the framework of personalized and precision medicine. Future directions include large-scale randomized controlled trials, pharmacokinetic optimization, and AI-driven predictive models to establish crocetin as a clinically viable neuroprotective agent.
Proteomic Characterization of Spinal Cord Myelin in the Mouse.
Schmitt O, Kaddatz H, Mikkat S … +3 more , Kipp M, Schümann A, Joost S
ASN Neuro · 2026 · PMID 41376199 · Full text
The myelin proteome is a critical structural and functional component of the central nervous system (CNS), undergoing dynamic remodeling throughout life. Pathological changes, such as those in multiple sclerosis, disrupt...
The myelin proteome is a critical structural and functional component of the central nervous system (CNS), undergoing dynamic remodeling throughout life. Pathological changes, such as those in multiple sclerosis, disrupt myelin integrity and lead to severe neurological deficits. Establishing a reproducible baseline of the CNS myelin proteome is therefore essential for monitoring alterations in disease models. Here, we present a comprehensive proteomic dataset of purified spinal cord myelin from healthy mice. Myelin fractions were isolated by preparative sucrose density centrifugation, followed by gel-free peptide separation and mass spectrometric analysis. Label-free quantification based on at least two tryptic peptides identified 725 proteins across six spinal cord samples. Comparison with previous large-scale datasets confirmed the robustness of our workflow. In particular, our dataset showed a 71% overlap with the 809 proteins identified by Jahn et al. using a highly similar proteomic approach. Importantly, there was near-complete agreement for canonical myelin proteins, validating both the specificity and reproducibility of our method. Beyond this shared core, our dataset contributed additional proteins, including axon- and glia-associated candidates, expanding the baseline repertoire of the spinal cord myelin proteome. In summary, this study establishes and validates a reliable workflow for spinal cord myelin proteomics and provides a reproducible reference dataset. While not yet including diseased tissue, this baseline is directly applicable to experimental models of demyelination and remyelination, offering a critical foundation for detecting and interpreting disease-related proteomic alterations in multiple sclerosis research.
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