Search Results (122)

Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox balance, and neuroinflammatory responses. These functions are closely linked to autophagic activity. The disruption of astrocytic autophagy contributes to synaptic dysfunction, chronic inflammation, myelin impairment, and blood–brain barrier instability. Dysregulation of astrocytic autophagy has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. This review summarizes the molecular mechanisms of autophagy in astrocytes and delineates its role in intercellular communication with neurons, microglia, oligodendrocytes, and endothelial cells. Furthermore, we will discuss current pharmacological approaches targeting astrocytic autophagy, with particular attention to repurposed agents such as rapamycin, lithium, and caloric restriction mimetics. Although promising in preclinical models, therapeutic translation is challenged by the complexity of autophagy’s dual roles and cell-type specificity. A deeper understanding of astrocytic autophagy and its crosstalk with other CNS cell types may facilitate the development of targeted interventions for neurodegenerative diseases. Full article

Brain pathophysiology in Down syndrome (DS), the most common genetic cause of intellectual disability, has traditionally been considered a consequence of neuronal dysfunction. However, although it is well documented that astrocytes play a critical role in brain homeostasis, synaptic regulation, and neuronal support, and their malfunction has been associated with the onset and progression of different neurological disorders, only a few studies have addressed whether astrocyte dysfunction can contribute to the DS pathophysiology. Astrocytes are increased in number and size, and show increased levels of expression of astroglial markers like S100β and GFAP. In this study, we detected a region-specific increase in astrocyte population in CA1 and, to a lesser extent, in the dentate gyrus. Single-nucleus transcriptomic profiling identified markers associated with reactive astroglia, synaptic transmission, and neuroinflammation in trisomic astrocytes. Functional analysis revealed abnormal Ca²⁺ oscillations in trisomic astrocytes and impaired astrocyte-to-neuron communication in CA1, the most affected subregion, leading to astrocyte-mediated excitatory synaptic depression. Our findings demonstrate that astrocytes play an active and critical role in the pathophysiology of DS, not only as reactive responders to neuronal injury but as key contributors to the disease process itself. This astrocytic dysfunction presents a region-specific distribution within the hippocampus, suggesting localized vulnerability and complex glial involvement in DS-related neuropathology. Full article

CD44, a structurally diverse cell-surface glycoprotein, plays a multifaceted and indispensable role in neural tissue across both physiological and pathological conditions. It orchestrates complex cell–extracellular matrix interactions and intracellular signaling through its variant isoforms and post-translational modifications and is broadly expressed in neural stem/progenitor cells, microglia, astrocytes, and selected neuronal populations. The interactions of CD44 with ligands such as hyaluronan and osteopontin regulate critical cellular functions, including migration, differentiation, inflammation, and synaptic plasticity. In microglia and macrophages, CD44 mediates immune signaling and phagocytic activity, and it is dynamically upregulated in neuroinflammatory diseases, particularly through pathways involving Toll-like receptor 4. CD44 expression in astrocytes is abundant during central nervous system development and in diseases, contributing to glial differentiation, reactive astrogliosis, and scar formation. Though its expression is less prominent in mature neurons, CD44 supports neural plasticity, circuit organization, and injury-induced repair mechanisms. Additionally, its expression at nervous system barriers, such as the blood–brain barrier, underscores its role in regulating vascular permeability during inflammation and ischemia. Collectively, CD44 emerges as a critical integrator of neural cell function and intercellular communication. Although the roles of CD44 in glial cells appear to be similar to those explored in other tissues, the expression of this molecule and its variants on neurons reveals peculiar functions. Elucidating the cell-type-specific roles and regulation of CD44 variants may offer novel therapeutic strategies for diverse neurological disorders. Full article

Intercellular communication in the central nervous system (CNS) is essential for maintaining neural function and coordinating responses to injury or disease. With recent advances in single-cell and spatial transcriptomics, a growing body of research has revealed that this communication is highly dynamic, shifting across states of health, aging, demyelination, and neurodegeneration. In this review, we synthesize the current findings on intercellular communication networks involving neurons, astrocytes, microglia, oligodendrocytes, and other glial populations in the CNS across four major states: healthy homeostasis, aging, demyelinating diseases, and Alzheimer’s disease (AD). We focus on how changes in intercellular communication contribute to the maintenance or disruption of CNS integrity and function. Mechanistic insights into these signaling networks have revealed new molecular targets and pathways that may be exploited for therapeutic intervention. By comparing the intercellular signaling mechanisms across different disease contexts, we underscore the importance of CNS crosstalk not only as a hallmark of disease progression, but also as a potential gateway for precision therapy. Full article

The ability of the neuropeptide oxytocin to affect glial cell function is receiving increasing attention. We previously reported that oxytocin at a low nanomolar concentration could inhibit both astrocytic Ca²⁺ signals and glutamate release. Here, we investigate the ability of oxytocin receptors to couple both inhibitory and stimulatory pathways in astrocytes, as already reported in neurons. We assessed the effects of oxytocin at concentrations ranging from low to high in the nanomolar range on intracellular Ca²⁺ signals and on the glutamate release in astrocyte processes freshly prepared from the striatum of adult rats. Our main findings are as follows: oxytocin could induce dual responses in astrocyte processes, namely the inhibition and facilitation of both Ca²⁺ signals and glutamate release; the inhibitory and the facilitatory response appeared dependent on activation of the G_i and the G_q pathway, respectively; both inhibitory and facilitatory responses were evoked at the same nanomolar oxytocin concentrations; and the biased agonists atosiban and carbetocin could duplicate oxytocin’s inhibitory and facilitatory response, respectively. In conclusion, due to the coupling of striatal astrocytic oxytocin receptors to different transduction pathways and the dual effects on Ca²⁺ signals and glutamate release, oxytocin could also play a crucial role in neuron–astrocyte bi-directional communication through a subtle regulation of striatal glutamatergic synapses. Therefore, astrocytic oxytocin receptors may offer pharmacological targets to regulate glutamatergic striatal transmission, which is potentially useful in neuropsychiatric disorders and in neurodegenerative diseases. Full article

Chronic migraine (CM) is a debilitating neurological disorder, yet the glial-specific mechanisms underlying its pathophysiology in the trigeminal nucleus caudalis (TNC)—a critical hub for craniofacial pain processing—remain poorly understood. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to resolve cell-type-specific transcriptional landscapes in a nitroglycerin (NTG)-induced CM rat model, with a particular focus on microglia and astrocytes. We identified 19 transcriptional clusters representing nine major cell types, among which reactive microglia (NTG-Mic) and astrocytes (NTG-Asts) were markedly expanded. The NTG-Mic displayed a glycolysis-dominant, complement-enriched state, whereas the NTG-Asts exhibited concurrent activation of amino acid transport and cytokine signaling pathways. Pseudotime trajectory analysis revealed bifurcated glial activation paths, with NTG driving both cell types toward terminal reactive states. Intercellular communication inference uncovered suppressed homeostatic interactions (e.g., CSF1-CSF1R) alongside enhanced proinflammatory signaling (e.g., FGF1-FGFR2, PTN-SDC4), particularly affecting neuron–glia and glia–glia crosstalk. Together, these findings define a high-resolution atlas of glial reprogramming in CM, implicating state-specific metabolic–immune transitions and dysregulated glial communication as potential targets for therapeutic intervention. Full article

Exosomes are extracellular vesicles secreted by almost all types of cells. Their release allows for the transport of specific regulatory cargo into the recipient cells and the modulation of their activity. Vesicular communication has also been identified as an important mechanism for the regulation of numerous cellular activities in the brain tissue, contributing to proper neuronal functions and brain homeostasis. In this work, we focus on the role of exosomes and extracellular vesicles in the communication between astrocytes and brain endothelial cells, two major components of the blood–brain barrier. We perform a comprehensive review of the latest studies highlighting the role of exosomes in astrocyte-endothelial cell crosstalk within the blood–brain barrier. We have also described the role of particular exosomal miRNAs in the regulation of astrocytes and brain endothelial cell functions, and discuss some future implications. Full article

Background/Objectives: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by challenges in social communication, restricted interests, and repetitive behaviors. Recent studies highlight the crucial roles of neuroglial cells—astrocytes, microglia, and oligodendrocytes—in synaptic function, neural connectivity, and neuroinflammation. These findings offer a fresh perspective on ASD pathophysiology. This review synthesizes current knowledge on neuroglial dysfunction in ASD, emphasizing its role in pathophysiological mechanisms, genetic influences, and potential therapeutic strategies. Methods: We conducted a comprehensive literature review, integrating insights from neuroscience, molecular biology, and clinical studies. Special focus was given to glial-mediated neuroinflammatory mechanisms, synaptic plasticity regulation, and the impact of genetic mutations on neuroglial signaling and homeostasis. Results: Neuroglial dysfunction in ASD is evident in abnormal synaptic pruning by microglia, impaired astrocytic glutamate regulation, and defective oligodendrocyte-driven myelination, which collectively disrupt neuronal architecture. Emerging therapies targeting these pathways, including anti-inflammatory drugs, microglial modulators, and cell-based approaches, show promise in alleviating key ASD symptoms. Additionally, advanced interventions such as gene editing and glial progenitor therapy present opportunities to correct underlying neuroglial dysfunction. Conclusions: This review establishes a comprehensive framework for understanding neuroglial contributions to ASD. By integrating insights from diverse disciplines, it enhances our understanding of ASD pathophysiology and paves the way for novel therapeutic strategies targeting neuroglial pathways. Full article

The dysfunction of mitochondria, the primary source of cellular energy and producer of reactive oxygen species (ROS), is associated with brain aging and neurodegenerative diseases. Scientific evidence indicates that light in the visible and near-infrared spectrum can modulate mitochondrial activity, a phenomenon known in medicine as photobiomodulation therapy (PBM-t). The beneficial effects of PBM-t on dementia and neurodegeneration have been reviewed in the literature. However, the molecular mechanisms underlying these findings have yet to be fully elucidated. This study investigates the mechanism behind dose-dependent glutamate release in nerve terminals after irradiation with 810 nm, 1 W for 60 s continuous, 1 cm², 1 W/cm², 60 J, 60 J/cm² (810 nm-1 W) or 810 nm, 0.1 W for 60 s continuous, 1 cm², 0.1 W/cm², 6 J, 6 J/cm² (810 nm-0.1 W), focusing on mitochondrial activities. The results show that PBM modulated the mitochondrial metabolism of cortical nerve terminals and supported a power-dependent increase in oxidative phosphorylation (OxPhos) activity when stimulated with pyruvate plus malate (P/M) or succinate (succ) as respiratory substrates. The PBM-induced increase in OxPhos was sensitive to adding rotenone (Complex I inhibitor) and antimycin A (Complex III inhibitor) when synaptosomes were stimulated with P/M, but only to antimycin A when stimulated with succ. This allowed us to observe that the glutamate efflux, disrupted in the presence of rotenone, was partially restored by PBM due to the increase in the OxPhos pathway led by Complex II. This evidence suggests that PBM, acting on mitochondria, could facilitate physiological communication within the neuron-astrocyte network through vesicular glutamate release, potentially regulating healthy brain function and brain dysfunction. Full article

Neuroinflammation is a complex and multifaceted process that involves dynamic interactions among various cellular and molecular components. This sophisticated interplay supports both environmental adaptability and system resilience in the central nervous system (CNS) but may be disrupted during neuroinflammation. In this article, we first characterize the key players in neuroimmune interactions, including microglia, astrocytes, neurons, immune cells, and essential signaling molecules such as cytokines, neurotransmitters, extracellular matrix (ECM) components, and neurotrophic factors. Under homeostatic conditions, these elements promote cellular cooperation and stability, whereas in neuroinflammatory states, they drive adaptive responses that may become pathological if dysregulated. We examine how neuroimmune interactions, mediated through these cellular actors and signaling pathways, create complex networks that regulate CNS functionality and respond to injury or inflammation. To further elucidate these dynamics, we provide insights using a multilayer network (MLN) approach, highlighting the interconnected nature of neuroimmune interactions under both inflammatory and homeostatic conditions. This perspective aims to enhance our understanding of neuroimmune communication and the mechanisms underlying shifts from homeostasis to neuroinflammation. Applying an MLN approach offers a more integrative view of CNS resilience and adaptability, helping to clarify inflammatory processes and identify novel intervention points within the layered landscape of neuroinflammatory responses. Full article

Communications between different cell types within a tissue are often critical for the proper functioning of an organ. In the central nervous system, interactions among neurons and glial cells are known to modulate neurotransmission, energy metabolism, extracellular ion homeostasis, and neuroprotection. Here we showed that bradykinin, a proinflammatory neuropeptide, can be detected by astrocytes, resulting in the secretion of cytokines that act on neurons. In astrocytic cell lines and primary astrocytes, bradykinin and several other ligands acting on G_q-coupled receptors stimulated Ca²⁺ mobilization, which subsequently led to the release of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). The bradykinin B₂ receptor antagonist, HOE-140, effectively blocked the ability of bradykinin to mobilize Ca²⁺ and stimulate mitogen-activated protein kinases (MAPKs) in astrocytes. Interestingly, incubation of neuronal cell lines and primary cortical neurons with conditioned media from bradykinin-treated astrocytes resulted in the activation of STAT3, a key component downstream of LIF and IL-6 receptors. LIF was apparently the major active factor in the conditioned media as the STAT3 response was almost completely neutralized by an anti-LIF antiserum. The presence of kininogen and kallikrein transcripts in neuronal cells but not in astrocytic cells indicates that neurons can produce bradykinin. Correspondingly, conditioned media from neuronal cells stimulated MAPKs in astrocytes in a HOE-140-sensitive manner. These studies demonstrate that paracrine signaling between neurons and astrocytes may involve ligands of G_q-coupled receptors and cytokines such as LIF. Full article

The synapse is a piece of information transfer machinery replacing the electrical conduction of nerve impulses at the end of the neuron. Like many biological mechanisms, its functioning is heavily affected by time constraints. The solution selected by evolution is based on chemical communication that, in theory, cannot compete with the speed of nerve conduction. Nevertheless, biochemical and biophysical compensation mechanisms mitigate this intrinsic weakness: (i) through the high concentrations of neurotransmitters inside the synaptic vesicles; (ii) through the concentration of neurotransmitter receptors in lipid rafts, which are signaling platforms; indeed, the presence of raft lipids, such as gangliosides and cholesterol, allows a fine tuning of synaptic receptors by these lipids; (iii) through the negative electrical charges of the gangliosides, which generate an attractive (for cationic neurotransmitters, such as serotonin) or repulsive (for anionic neurotransmitters, such as glutamate) electric field. This electric field controls the flow of glutamate in the tripartite synapse involving pre- and post-synaptic neurons and the astrocyte. Changes in the expression of brain gangliosides can disrupt the functioning of the glutamatergic synapse, causing fatal diseases, such as Rett syndrome. In this review, we propose an in-depth analysis of the role of gangliosides in the glutamatergic synapse, highlighting the primordial and generally overlooked role played by the electric field of synaptic gangliosides. Full article

Sexual dimorphism refers to biological differences between males and females in the same species, including morphological, physiological, and behavioral characteristics. Steroid hormones are associated with changes in several brain regions, as well as the pathophysiology of aging, obesity, and neuropsychiatric diseases. The hypothalamus controls several physiological processes, including metabolism, reproduction, circadian rhythm, and body homeostasis. Refined communication between neurons and glial cells, particularly astrocytes, coordinates physiological and behavioral hypothalamic functions. Therefore, from previously published studies, this review aims to highlight sex-related differences in rodent hypothalamic astrocytes, since we believe that this brain region is essential for the understanding of dimorphic patterns that are influenced by steroid sex hormones. Thus, we review concepts of sexual dimorphism, the hypothalamic-pituitary-gonadal axis, the role of hormonal influence on hypothalamic astrocyte functions, neuroglial communication, as well as sexual dimorphism and neuropsychiatric disorders and glioprotective mechanisms associated with the hypothalamus. Full article

The human central nervous system is convolutedly connected to the gut microbiome, a diverse community of microorganisms residing in the gastrointestinal tract. Recent research has highlighted the bidirectional communication between the gut microbiome and neuroglial cells, which include astrocytes, microglia, oligodendrocytes, and ependymal cells. These neuroglial cells are essential for maintaining CNS homeostasis, supporting neuronal function, and responding to pathological conditions. This review examines the interactions between the gut microbiome and neuroglia, emphasizing their critical roles in brain health and the development of neurological disorders. Dysbiosis, or imbalance in the gut microbiome, has been associated with various neurological and psychiatric conditions, such as autism spectrum disorder, anxiety, depression, and neurodegenerative diseases like Alzheimer’s and Parkinson’s. The microbiome influences brain function through microbial metabolites, immune modulation, and neuroinflammatory responses. Understanding these interactions paves the way for new therapeutic targets and strategies for preventing and treating CNS disorders. This scoping review aims to highlight the mechanisms of the microbiome-neuroglia axis in maintaining brain health and its potential as a therapeutic target. Full article

Neural precursor cells (NPCs) that persist in the postnatal/adult subventricular zone (SVZ) express connexins that form hemichannels and gap junctions. Gap junctional communication plays a role in NPC proliferation and differentiation during development, but its relevance on postnatal age remains to be elucidated. In this work we aimed to evaluate the effect of the blockade of gap junctional communication on proliferation and cell fate of NPCs obtained from the SVZ of postnatal rats. NPCs were isolated and expanded in culture as neurospheres. Electron microscopy revealed the existence of gap junctions among neurosphere cells. Treatment of cultures with octanol, a broad-spectrum gap junction blocker, or with Gap27, a specific blocker for gap junctions formed by connexin43, produced a significant decrease in bromodeoxyuridine incorporation. Octanol treatment also exerted a dose-dependent antiproliferative effect on glioblastoma cells. To analyze possible actions on NPC fate, cells were seeded in the absence of mitogens. Treatment with octanol led to an increase in the percentage of astrocytes and oligodendrocyte precursors, whereas the percentage of neurons remained unchanged. Gap27 treatment, in contrast, did not modify the differentiation pattern of SVZ NPCs. Our results indicate that general blockade of gap junctions with octanol induces significant effects on the behavior of postnatal SVZ NPCs, by reducing proliferation and promoting glial differentiation. Full article