ASN NEURO最新文献

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_A (muscimol, gabazine) and GABA_B receptors (baclofen, CGP55845). VEGF-A expression and secretion were analyzed by immunofluorescence, western blot, RT-qPCR, and ELISA. To assess Ca²⁺ involvement, we used Ca²⁺-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 Vegfa mRNA. Both effects were abolished by extracellular Ca²⁺ removal or nimodipine, indicating a Ca²⁺-dependent mechanism. FR180204 also attenuated GABA- and GABA_A-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 Ca²⁺- and GABA_A-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.

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.

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.

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. In vivo, acoustic startle behavioral testing was used to measure startle reaction and prepulse inhibition in both groups. Raclopride, a D₂ receptor antagonist, decreased population spike amplitude in control but not Thy1 KO slices. Quinpirole, a D₂ receptor agonist, did not change spike amplitude in any group. Gabapentin, a Ca²⁺ 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.

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.

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 Gardenia jasminoides, 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.

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 chGLAST 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_Max and a non-significant change in K_M, changes in V_Max reflect alterations in plasma membrane transporter numberinity. Pharmacological analysis revealed the involvement of the phosphatidyl inositol 3 kinase (PI3K), the Ca²⁺/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 chglast 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.

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.

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^B-/- 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.

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 g 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 g 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 g ratios clinically in both physiologic and pathophysiologic studies necessitates calibration with electron microscopy-derived g 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.