Neuroglia

Background/Objective: Parkinson’s disease (PD) has long been viewed from a neurocentric perspective; however, increasing evidence indicates that glial dysfunction also contributes to dopaminergic neurodegeneration. Although neurotoxic glial phenotypes have been described in amyotrophic lateral sclerosis and Alzheimer’s disease in vivo models, it remains unclear whether similar states arise in the pathological milieu of PD. This study aimed to determine whether glial cells with intrinsic neurotoxic properties emerge in the substantia nigra pars compacta (SNpc) in a PD context. Methods: The classical 6-hydroxydopamine rat model was used to obtain glial cultures from the ipsilateral, toxin-damaged SNpc. These cultures were characterized by quantifying cell number and morphology, as well as by assessing the expression of glial markers. Their neurotoxic potential was evaluated in vitro through co-cultures with PC12 cells, and in vivo by transplanting the isolated cells into the SNpc of naïve rats. Assessments included PC12 cell survival, and integrity of the nigrostriatal pathway and motor performance in the cylinder test. Results: Ipsilateral SNpc cultures yielded 25-fold more cells than contralateral controls. Cultured cells co-expressed astrocytic and microglial markers, thus defining a population of damage-derived reactive glia (DDRG). When co-cultured, DDRG reduced PC12 cell survival, whereas control glial cells showed no neurotoxic effects. In vivo, DDRG transplantation induced a dose-dependent loss of dopaminergic neurons and motor impairments, while vehicle and control glia produced no detectable effects. Conclusions: Our findings suggest that glial cells emerging from a neuroinflammatory/neurodegenerative environment in the SNpc may contribute to dopaminergic neuron loss. Within the context of the experimental PD model used, DDRG appears to represent a glial population with potential pathogenic relevance and may constitute a candidate target for further investigation as a therapeutic strategy in Parkinson’s disease. Full article

COVID-19 has raised significant concern regarding its neurological impact, particularly during the early pandemic waves when severe systemic inflammation and neuroimmune dysregulation were more common. Although SARS-CoV-2 has been extensively studied, the precise mechanisms underlying its neurological effects remain incompletely understood, and much of the available evidence is derived from early variants with higher pathogenicity. Current research indicates that neuroinflammatory processes—driven primarily by systemic cytokine elevation, microglial activation, and blood–brain barrier dysfunction—contribute to a wide range of neurological symptoms. Severe complications such as encephalopathy, stroke, and cognitive impairment were predominantly reported in critically ill patients infected with the Wuhan, Alpha, or Delta variants, while such manifestations are considerably less frequent in the Omicron era. Most proposed mechanisms, including ACE2-mediated viral entry into the central nervous system, are supported mainly by experimental or preclinical studies rather than definitive human evidence. Biomarkers such as IL-6 and TNF-α, along with neuroimaging modalities including MRI and PET, offer useful but indirect indicators of neuroinflammation. Therapeutic approaches continue to focus on controlling systemic inflammation through immunomodulatory agents, complemented by targeted non-pharmacological strategies—such as physical rehabilitation, cognitive support, and psychological interventions—for the minority of patients with persistent neurological deficits. Overall, current evidence supports a variant-dependent neuroinflammatory profile and underscores the need for longitudinal, mechanism-focused studies to better characterize long-term neurological outcomes and refine therapeutic strategies. Full article

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways. Full article

Background/Objectives: A healthy lifestyle based on a balanced diet promotes overall well-being and supports brain health, while the consumption of high-energy foods can negatively affect cognitive function, particularly during early developmental stages, such as adolescence. Astrocytes are essential for brain homeostasis, including modulation of neurogenesis in the hippocampus, a region involved in cognitive functions. The impact of short-term high-fat diet (HFD) exposure on astrocytes during adolescence remains unclear. In this study, we examined if brief periods of HFD influence astrocyte morphology, density, and territory volume and, in parallel, the maturation of doublecortin-positive (DCX⁺) cells in the dorsal hippocampus of adolescent male mice. Methods: We performed 3D reconstructions, analyzed morphometric features as well as other parameters of astrocytes and DCX⁺ cells following 1 week of HFD (1 w-HFD), 2 weeks of HFD (2 w-HFD), and 1 week of HFD followed by 1 week of return to a low-fat diet (1 w-HFD – 1w-LFD). Results: We observed that 1 w-HFD significantly increased astrocyte morphological complexity and density compared with the control group (1 w-LFD). After 2 w-HFD, astrocyte complexity declined, whereas density was unchanged. Notably, in the 1 w-HFD – 1 w-LFD group, astrocyte complexity was comparable to that of the 2 w-HFD group; density increased compared to both control groups (2 w-LFD and 2 w-HFD). Moreover, both 1 w- and 2 w-HFD impaired granular cell layer (GCL) DCX⁺ cells density and maturation, and a return to LFD after 1 w-HFD restored maturation but not density. Conclusions: Altogether, these data suggest that short-term HFD exposure has complex effects on GCL astrocytes and impairs DCX⁺ cell maturation in the dorsal hippocampus of adolescent mice. Full article

Introduction: This study investigates how early aging affects the rat brain, focusing on aquaporin-4 and IL-17 levels in the whole brain, as well as glial cell alterations in the hippocampus. The hippocampus, essential for learning and memory, undergoes age-related changes contributing to cognitive decline and neuroinflammation. Glial cells—particularly microglia and astrocytes—are central to these processes. Most research focuses on advanced aging; in this study, we examine early aging effects. Methods: Male Wistar rats (13 weeks and 13 months old) were used. Whole-brain IL-17 and aquaporin-4 levels were assessed by ELISA. Immunohistology targeting GFAP, Iba1, and CD31 was performed on hippocampal sections to assess glial and vascular changes in CA1, CA2/3, and the dentate gyrus (DG). Results: Middle-aged rats brains showed significantly higher IL-17 and aquaporin-4 levels, confirming low-grade inflammation and metabolic alteration. In the hippocampus, microglia, astrocytes, and cerebral microvessels increased in CA2/3, with no significant changes in CA1 or DG. Conclusions: Early aging induces whole-brain neuroinflammation and metabolic changes and region-specific hippocampal alterations, with CA2/3 being particularly susceptible. These findings advance understanding of early brain aging and highlight CA2/3 as a potential target for intervention. Full article

Oligodendrocytes (OLs) constitute the main glial population in the central nervous system and are indispensable for the stability and performance of neural networks. Although best known for generating and maintaining myelin to speed impulse conduction, their influence extends further. By modulating myelin in response to activity, supplying metabolic substrates, and engaging in neuroimmune communication, OLs help preserve the structural integrity and plasticity of neuronal circuits. Growing evidence now positions defective OLs as central players in Alzheimer’s disease (AD). Experimental work suggests that OL injury can act as an early trigger, fostering amyloid-β (Aβ) deposition and Tau hyperphosphorylation. Conversely, toxic Aβ aggregates and pathological Tau proteins damage OLs, causing myelin breakdown and progressive neurodegeneration that fuels a self-perpetuating cycle. Here, we synthesize current knowledge of OL physiology and its multifaceted contributions to AD pathogenesis, with particular attention to the bidirectional interplay between OL dysfunction and the disease’s core features—Aβ and tau. On this basis, we outline prospective therapeutic avenues to protect or restore oligodendrocyte function in AD. Full article

Maternal immune activation (MIA) during pregnancy has been associated with increased risk of fetal loss and neurodevelopmental disorders in offspring. This review summarizes recent findings on the effects of MIA on fetal survival and microglial phenotype. Studies using polyinosinic–polycytidylic acid [poly(I:C)-induced MIA mouse models have revealed the crucial role of interleukin-17A (IL-17A) in mediating these effects. Overexpression of RORγt, a key transcription factor for IL-17A production, enhances poly(I: C)-induced fetal loss, possibly due to increased placental vulnerability. Intraventricular administration of IL-17A in fetal brains activates microglia and alters their localization, particularly in periventricular regions and the medial cortex. These activated microglia may contribute to abnormal synaptic pruning and excessive phagocytosis of neural progenitor cells, potentially leading to long-term neurodevelopmental abnormalities. The insights gained from MIA research have important clinical implications, including the potential for early identification of high-risk pregnancies and the development of novel preventive and therapeutic strategies. Future research should focus on elucidating the roles of other cytokines, determining critical periods of MIA susceptibility, and translating findings to human populations, while carefully considering ethical implications and the need for appropriate risk communication. Full article

Background: Glioblastoma (GBM) remains refractory to chemoradiotherapy. Glial populations—microglia/monocyte-derived macrophages, reactive astrocytes, and the oligodendrocyte lineage—shape both treatment resistance and radiation-related brain injury. Scope: We synthesize how myeloid ontogeny and plasticity, astrocytic hubs (IL-6/STAT3, TGF-β, connexin-43/gap junctions), and oligodendrocyte precursor cells (OPCs)–linked programs intersect with DNA-damage responses, hypoxia-driven metabolism, and extracellular vesicle signaling to support tumor fitness while predisposing normal brain to radiotoxicity. Translational implications: Convergent, targetable pathways (IL-6/JAK–STAT3, TGF-β, chemokine trafficking, DDR/senescence) enable co-design of radiosensitization and neuroprotection. Pragmatic levers include myeloid reprogramming (CSF-1R, CCR2), astrocyte-axis modulation (STAT3, TGF-β, Cx43), and brain-penetrant DDR inhibition (e.g., ATM inhibitors), paired with delivery strategies that raise intratumoral exposure while sparing healthy tissue (focused-ultrasound blood–brain barrier opening, myeloid-targeted dendrimers; Tumor Treating Fields as an approved adjunct therapy). Biomarker frameworks (TSPO-PET, macrophage-oriented MRI radiomics, extracellular vesicle liquid biopsy) can support selection and pharmacodynamic readouts alongside neurocognitive endpoints. Outlook: Timing-aware combinations around radiotherapy and hippocampal/white-matter sparing offer a near-term roadmap for “glia-informed” precision radiotherapy. Full article

Background: During development, reelin sets the pace of neocortical neurogenesis, enabling newborn neurons to migrate. However, whether—and, if so, how—reelin signaling affects the adult neurogenic niches remains uncertain. Methods: In the present study, we use both loss- and gain-of-function genetic approaches, along with in vivo and ex vivo assays, to investigate this question. Results: We show that reelin signaling, resulting in Dab1 phosphorylation, occurs in the ependymal-subependymal zone (EZ/SEZ) of the lateral ventricles, where, along with its associated rostral migratory stream (RMS), the highest density of functional ApoER2 accumulates. Mice deficient in Reelin, ApoER2, or Dab1 exhibit enlarged ventricles and a dysplastic RMS. Moreover, while the conditional ablation of Dab1 in neural progenitor cells (NPCs) enlarges the ventricles and impairs neuroblast clearance from the SEZ, the transgenic misexpression of Reelin in NPCs of Reelin-deficient mice normalizes the ventricular lumen and the density of ependymal cilia, thereby ameliorating neuroblast migration. Consistently, intraventricular infusion of reelin reroutes neuroblasts. Conclusions: These results demonstrate that reelin signaling persists, sustaining the germinal niche of the lateral ventricles and influencing neuroblast migration in the adult brain. Full article

Major Depressive Disorder (MDD) remains a leading cause of disability worldwide, perpetuated by an incomplete understanding of its pathophysiology and the limited efficacy of conventional antidepressants. Historically, research has focused on neuron-centric models, particularly the monoamine hypothesis. However, the field is now recognizing the critical role of glial cells such as astrocytes, microglia, and oligodendrocytes, establishing them as key contributors to the molecular basis of depression. Rather than serving solely supportive roles, these cells actively modulate neuroinflammation, synaptic plasticity, neurotransmitter homeostasis, and metabolic regulation, processes disrupted in MDD. We discuss how stress-induced epigenetic modifications such as histone acetylation, methylation, and DNA methylation are linked to alterations in astrocytic glutamate transport, microglial inflammatory states, and oligodendrocyte-mediated myelination. Special emphasis is placed on the concept of glial transcriptional plasticity, whereby environmental adversity induces durable and cell type specific gene expression changes that underlie neuroinflammation, excitatory–inhibitory imbalance, and white matter deficits observed in MDD. By integrating findings from postmortem human tissue, single-cell omics, and stress-based animal models, this review highlights converging molecular mechanisms linking stress to glial dysfunction. We further outline how targeting glial transcriptional regulators may provide new therapeutic avenues beyond conventional monoaminergic approaches. Full article

Background/Objectives: Compartmentalized glucose metabolism in the brain contributes to neuro-metabolic stability and shapes hypothalamic control of glucose homeostasis. Glucose transporter-2 (GLUT2) is a plasma membrane glucose sensor that exerts sex-specific control of hypothalamic astrocyte glucose and glycogen metabolism. Aging causes counterregulatory dysfunction. Methods: The current research used Western blot and HPLC–electrospray ionization–mass spectrometry to investigate whether aging affects the GLUT2-dependent hypothalamic astrocyte metabolic sensor, glycogen enzyme protein expression, and glycogen mass according to sex. Results: The data document GLUT2-dependent upregulated glucokinase (GCK) protein in glucose-deprived old male and female astrocyte cultures, unlike GLUT2 inhibition of this protein in young astrocytes. Glucoprivation of old male and female astrocytes caused GLUT2-independent downregulation of 5′-AMP-activated protein kinase (AMPK) protein, indicating loss of GLUT2 stimulation of this protein with age. This metabolic stress also caused GLUT2-dependent suppression of phospho-AMPK profiles in each sex, differing from GLUT2-mediated glucoprivic enhancement of activated AMPK in young male astrocytes and phospho-AMPK insensitivity to glucoprivation in young female cultures. GS and GP isoform proteins were refractory to glucoprivation of old male cultures, contrary to downregulation of these proteins in young glucose-deprived male astrocytes. Aging elicited a shift from GLUT2 inhibition to stimulation of male astrocyte glycogen accumulation and caused gain of GLUT2 control of female astrocyte glycogen. Conclusions: The outcomes document sex-specific, aging-related alterations in GLUT2 control of hypothalamic astrocyte glucose and ATP monitoring and glycogen mass and metabolism. These results warrant future initiatives to assess how these adjustments in hypothalamic astrocyte function may affect neural operations that are shaped by astrocyte–neuron metabolic partnership. Full article

Background/Objectives: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor associated with poor survival outcomes. Given the significant financial burden of cancer treatments, repurposing existing drugs can reduce costs and enhance therapeutic efficacy. Metformin, an antidiabetic medication, has been investigated for its antineoplastic effects against GBM. Here, we reviewed the in vitro and in vivo effects of metformin through GBM cell viability and overall animal survival, respectively. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data extraction and statistical analyses were performed using Microsoft Excel, and R. Effect sizes were calculated as standard mean differences (SMDs) for in vitro studies assessing cell viability and hazard ratios (HRs) for in vivo mice survival analyses. Results: A total of two-hundred-thirty in vitro studies and five-hundred-sixty-six in vivo studies were screened. Of these, seven in vitro and eight in vivo studies were compatible for the meta-analysis. The random-effects model showed a reduction in cell viability (SMD [95% CI]: 3.70 [2.28, 5.12]). A pooled in vivo survival analysis suggests an increase in overall survival in mice receiving metformin (p-value = 0.055). A random-effects model for overall survival supports this pooled analysis (HR [95% CI]: 0.76 [0.39, 1.46]). Additionally, metformin also showed a reduction in cell viability (SMD [CI]; 2.27 [0.79, 3.75]) and an increase in overall animal survival (HR [CI], 0.23 [0.12, 0.45]) when it was added as an adjuvant to traditional GBM therapies. Conclusions: Our findings from in vitro and in vivo studies support the potential of metformin as an antineoplastic agent against GBM. We plan to extend our analyses into clinical studies to determine if these benefits extend to human patients. Metformin has the potential to revolutionize GBM therapy if a relationship exists due to its inexpensive nature. Full article

Background: Primary spinal gliomas are rare in the pediatric population. Separately, FGFR1 genomic aberrations are also uncommon in spinal cord tumors. We report a case of a previously well adolescent who presented with progressive symptoms secondary to an intramedullary tumor with unique radiological and molecular characteristics. Case Presentation: A previously well 17-year-old male presented with worsening mid-back pain associated with lower limb long-tract signs. Magnetic resonance imaging (MRI) of his neuro-axis reported a long-segment intramedullary lesion with enhancing foci and a multi-septate syrinx containing hemorrhagic components from C4 to T12. The largest enhancement focus was centered at T7. Additional MRI sequences observed no intracranial involvement or vascular anomaly. He underwent an emergent laminoplasty and excision of the thoracic lesion. Intraoperative findings demonstrated a soft, grayish intramedullary tumor associated with extensive hematomyelia that had multiple septations. Active fenestration of the latter revealed blood products in various stages of resolution. Postoperatively, the patient recovered well, with neurological improvement. Final histology reported a circumscribed low-grade glial neoplasm. Further molecular interrogation via next-generation sequencing panels showed FGFR1 p.K656E and V561M alterations. The unique features of this case are presented and discussed in corroboration with a focused literature review. Conclusions: We highlight an interesting case of an intramedullary tumor with unusual radiological and pathological findings. Emphasis is on the importance of tissue sampling in corroboration with genomic investigations to guide clinical management. Full article

Astrocytes are the most common type of glial cell in the central nervous system (CNS). They have many different functions that go beyond just supporting other cells. Astrocytes were once thought of as passive parts of the CNS. However, now they are known to be active regulators of homeostasis and active participants in both neurodevelopmental and neurodegenerative processes. This article looks at the both sides of astrocytic function: how they safeguard synaptic integrity, ion and neurotransmitter balance, and blood-brain barrier (BBB) stability, as well as how astrocytes can become activated and participate in the immune response by releasing cytokines, upregulating interferons, and modulating the blood–brain barrier and inflammation disease condition. Astrocytes affect and influence neuronal function through the tripartite synapse, gliotransmission, and the glymphatic system. When someone is suffering from neurological disorders, reactive astrocytes become activated after being triggered by factors such as pro-inflammatory cytokines, chemokines, and inflammatory mediators, these reactive astrocytes, which have higher levels of glial fibrillary acidic protein (GFAP), can cause neuroinflammation, scar formation, and the loss of neurons. This review describes how astrocytes are involved in important CNS illnesses such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia. It also emphasizes how these cells can change from neuroprotective to neurotoxic states depending on the situation. Researchers look at important biochemical pathways, such as those involving toll-like receptors, GLP-1 receptors, and TREM2, to see if they can change how astrocytes respond. Astrocyte-derived substances, including BDNF, GDNF, and IL-10, are also essential for protecting and repairing neurons. Astrocytes interact with other CNS cells, especially microglia and endothelial cells, thereby altering the neuroimmune environment. Learning about the molecular processes that control astrocytic plasticity opens up new ways to treat glial dysfunction. This review focuses on the importance of astrocytes in the normal and abnormal functioning of the CNS, which has a significant impact on the development of neurotherapeutics that focus on glia. Full article

Neurodegenerative diseases are characterized by progressive loss of neurons and remain largely incurable. Numerous mammalian models have been developed to study the mechanisms underlying their physiopathology; however, their high cost, complexity and time requirements highlight the need for alternative systems. Glial cells are increasingly recognized as key contributors to neurodegenerative disease progression through non-cell autonomous mechanisms. Planarians possess a nervous system with diverse neuronal subtypes and glial cells, offering an attractive combination of evolutionary conservation and remarkable regenerative capacity. Unlike mammalian glia, planarian glia originate from phagocytic progenitors and exhibit distinctive molecular markers, including if-1, cali and cathepsin. Emerging evidence suggests that planarian glia may contribute to neurotransmitter homeostasis, neuron–glia interactions and phagocytic activity. Additionally, planarians display robust and quantifiable behavioral responses, making them well suited for modeling neurodegenerative disease. In this review, we summarize the current findings regarding neuronal subtypes and glial cells in planaria, emphasizing their relevance as a model system. Further research into planarian glia will be crucial for understanding their roles in pathological contexts and for exploring their potential applications in neurodegenerative diseases research. Planarian simplicity, regenerative capacity, and compatibility with high-throughput approaches position planarians as a powerful model for investigating the cellular and molecular mechanisms underlying neurodegenerative diseases and for identifying potential therapeutic targets. Full article

Background/Objectives: Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Experimental models that replicate core features of PD are critical to investigate underlying mechanisms and therapeutic strategies. Here we evaluated the effects of an acute unilateral intrastriatal lesion induced by 6-hydroxydopamine (6-OHDA) on neuronal loss and the associated inflammatory response. Methods: Adult male Wistar rats received an injection of 6-OHDA into the right striatum, while the contralateral side received vehicle. Motor behavior was assessed by cylinder and open field tests on post-lesion days (PLDs) 7 and 14. Brains were analyzed by immunohistochemistry for tyrosine hydroxylase (TH), glial response (GFAP and Iba1), and caspase-3 at PLD +14. Results: A marked reduction in TH-immunoreactivity in the lesioned striatum was observed, with ~40% loss of TH-positive neurons in the ipsilateral SNpc. Surviving neurons displayed a 28% increase in soma size compared to the contralateral side. The lesion was accompanied by robust astrocytic and microglial activation at the injection site, as well as enhanced GFAP immunoreactivity in the ipsilateral SN pars reticulata. Apoptotic profiles emerged in the SNpc at PLD +14. Functionally, these alterations were reflected in significant motor asymmetry and decreased locomotor activity. Conclusions: Our findings demonstrate that neuroinflammation accompanies early dopaminergic degeneration following intrastriatal 6-OHDA administration, contributing to motor deficits. Future studies with older animals and broader behavioral and anatomical assessments—including regions such as the ventral tegmental area and motivational or anxiety-related paradigms—may enhance translational relevance. Full article

Neuropeptides (NPs) are small molecular messengers synthesized in large dense core vesicles (LDCVs) and secreted to the extracellular space. In the central nervous system (CNS), NPs are secreted to the synaptic space, playing crucial roles in modulating neurons, astrocytes, microglia, oligodendrocytes, and other glial cells, through G-protein-coupled receptors, thereby influencing complex multicellular responses. During neuroinflammation, NPs regulate glial and neuronal reactions to inflammatory signals, promoting resolution and preventing chronic, non-resolving inflammation. For example, NPs inhibit apoptosis in neurons and oligodendrocytes while inducing anti-inflammatory effects in microglia and astrocytes, modulating cytokine secretion. Here, we present the notion that neuropeptides could participate in neuroinflammatory progression, altering glial responses, leading to excessive, non-resolutive inflammation when dysregulated. NP signaling—whether excessive or deficient—can disrupt specific cellular processes, leading to pathological inflammation, gliosis, and functional loss—hallmarks of neurodegenerative diseases. Despite their significance, the precise mechanisms underlying NP-mediated effects remain incompletely understood. This review synthesizes experimental and translational evidence highlighting the pivotal role of NPs in resolving neuroinflammation and explores how targeting NPs or their receptors could offer novel therapeutic strategies for neurodegenerative disorders. Further research is needed to elucidate the specific signaling pathways and receptor dynamics involved, which could pave the way for innovative treatments that address the root causes of these debilitating conditions. Full article

Neurodevelopmental disorders represent a significant health concern, leading to a wide range of clinical, cognitive, and social impairments. Although the exact causes of these disorders remain unclear, genetic, epigenetic, and environmental factors all contribute to their emergence. Recently, the role of neuroglia in the pathophysiology of these conditions has received increasing attention. Various glial mechanisms (e.g., neuroinflammation, neurotransmitter regulation, gliosis) have been implicated in both shared and distinct features of these disorders. The identification of novel etiological factors may facilitate the development of new therapeutic modalities targeting glial dysfunction. This review provides a comprehensive overview of neuroglia and summarizes the current understanding of neurodevelopmental disorders and co-occurring disruptive behavioral disorders from a glial perspective. Furthermore, gaps in the literature are highlighted, and potential strategies for addressing these gaps and integrating findings into clinical practice are discussed. Full article

Background/Objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST). Methods: We analyzed the proteome in cortical–hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs). Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated. Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression. Full article