Glia最新文献

Oligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS) are capable of proliferating, migrating, and differentiating into oligodendrocytes. OPCs are crucial for the myelination of axons during development and remyelination after injury in adulthood. OPCs also play important roles in promoting angiogenesis, neurotrophy, and immunomodulation, which makes them a relevant element of regenerative approaches for many CNS diseases, especially demyelinating ones. OPC migration is important during neurodevelopment and regeneration, and as such is regulated by a multitude of intracellular and extracellular factors. Identifying these factors will facilitate the optimized regulation of OPC migration and thus enhance therapeutic effects. This field is a current research hotspot, and new findings are constantly emerging. Here, we comprehensively review research progress on the regulatory factors that control OPC migration.

A greater understanding of the neurobiology of nicotine is needed to reduce or prevent chronic addiction, ameliorate detrimental nicotine withdrawal effects, and improve cessation rates. Nicotine binds and activates two astrocyte-expressed nicotinic acetylcholine receptors (nAChRs), α4β2 and α7. Protein kinase B-β (Pkb-β or Akt2) expression is restricted to astrocytes in mice and humans and is activated by nicotine. To determine if AKT2 plays a role in astrocytic nicotinic responses, we generated astrocyte-specific Akt2 conditional knockout (cKO) and full Akt2 KO mice. For in/ex vivo studies, we examined mice exposed to chronic nicotine for 2 weeks in drinking water (200 μg/mL) or following acute nicotine challenge (0.09, 0.2 mg/kg) after 24 h. Our in vitro studies used cultured mouse astrocytes to measure nicotine-dependent astrocytic responses. Sholl analysis was used to measure glial fibrillary acidic protein responses in astrocytes. Our data show wild-type (WT) mice exhibit increased astrocyte morphological complexity during acute nicotine exposure, with decreasing complexity during chronic nicotine use, whereas Akt2 cKO mice showed enhanced acute responses and reduced area following chronic exposure. In culture, we found 100 μM nicotine sufficient for morphological changes and blocking α7 or α4β2 nAChRs prevented observed morphological changes. We performed conditioned place preference (CPP) in Akt2 cKO mice, which revealed reduced nicotine preference in cKO mice compared to controls. Finally, we performed RNASeq comparing nicotine- and LPS-mediated gene expression, identifying robust differences between these two astrocytic stimuli. These findings show the importance of nAChRs and AKT2 signaling in the astrocytic response to nicotine.

Multiple sclerosis (MS) is the most common non-infectious inflammatory CNS disease, characterized by progressive neurodegeneration and focal demyelinated lesions. Traditionally considered an autoimmune disease, MS is driven by the immune system's attack on CNS myelin, resulting in cumulative disability. However, conventional anti-inflammatory treatments often fail to prevent progressive deterioration, particularly in the absence of overt inflammation, highlighting the need for a deeper understanding of its pathogenesis. Recent research has revealed a more complex disease mechanism involving both peripheral immune responses and intrinsic CNS factors, with glial cells playing a central role. Persistent inflammation in MS is associated with mixed active/inactive lesions dominated by microglia and astrocyte dysregulation. These glial populations exhibit maladaptive activation, contributing to failed remyelination and ongoing neurodegeneration. Transcriptomic and epigenomic alterations as well as aging further exacerbate glial dysfunction, creating a self-perpetuating cycle of inflammation and damage. Emerging evidence suggests that the interplay between peripheral immune cells and glial populations and the potential dual-use nature of molecular tools shared by the immune system and CNS disrupts homeostatic signaling, leading to a loss of tissue integrity. This review synthesizes findings on glial cell biology in MS, with a focus on microglia and astrocytes, while addressing their roles in demyelination, synapse loss, and neurodegeneration. The limitations of animal models, particularly EAE, in replicating the complexity of MS are also addressed. Finally, critical questions are outlined to guide future research into glial pathology and to identify novel therapeutic approaches targeting progressive MS.

Microglia, the resident immune cells of the central nervous system (CNS), are in constant survey of their environment. Extracellular nucleotides, released by stressed and damaged neurons, act as danger signals to microglia through various purinergic/pyrimidinergic receptors. In the CNS, the UDP receptor P2Y6 is mostly expressed in microglia, where its activation induces phagocytosis, a homeostatic function that is dysregulated in several neurodegenerative diseases and in chronic pain. Yet, modulatory mechanisms impacting P2Y6 activity remain to be identified. The microglial β2 adrenergic receptor (ADRB2) for norepinephrine represents a promising candidate for modulation of P2Y6 receptors. Our calcium imaging data indicate that exposure to the ADRB2 agonist isoproterenol inhibits the calcium transients evoked by activation of Gq-coupled P2Y6 receptors in primary mouse microglia. This functional modulation, suppressed by the selective ADRB2 antagonist ICI-118551, is conserved in human iPSC-derived microglia. Accordingly, we observed that the phagocytotic activity induced by P2Y6 is reduced by ADRB2 signaling in both mouse and human microglia. Finally, we report that ADRB2 activation is linked to a decrease in P2Y6 mRNA expression. These findings provide evidence that metabotropic and transcriptional crosstalks between nucleotide and adrenergic transductions control microglial responses in the CNS, potentially contributing to the pathophysiology of neuro-immune disorders and chronic pain conditions.

A disproportionate percentage of adolescents are diagnosed with human immunodeficiency virus (HIV) in the United States each year. Preexposure prophylaxis (PrEP), an antiretroviral regimen, is effective at preventing the transmission of HIV to adolescents at substantial risk for acquiring HIV. However, other select antiretrovirals have been shown to cause white matter deficits in experimental models. Adolescents taking PrEP are uniquely vulnerable to myelin impairments as the adolescent brain undergoes high rates of myelination. Here, we report that PrEP significantly reduced oligodendrocyte maturation in adolescent rats. Furthermore, cultures of primary rat oligodendrocyte progenitors treated with PrEP showed inhibited oligodendrocyte differentiation through deacidification of lysosomes resulting in lysosomal accumulation of myelin proteins. Acidic nanoparticle co-administration with PrEP prevented PrEP-induced oligodendrocyte maturation impairments both in vivo and in vitro. These studies suggest uninfected adolescents are vulnerable to PrEP-induced oligodendrocyte impairments and identify maintenance of lysosome pH as a critical factor in antiretroviral design.

Status epilepticus (SE) is a severe condition that results in uncontrollable cerebral edema and cognitive dysfunction. Recent studies suggest that the localization of aquaporin-4 (AQP4) in astrocytic endfeet plays a crucial role in regulating blood-brain water transport and cell volume control, particularly along perivascular pathways. However, the signaling mechanisms underlying AQP4 localization remain poorly understood. In this study, we utilized the genetically encoded fluorescent calcium (Ca²⁺) indicator GCaMp6f to investigate Ca²⁺ signals in astrocytic somata, processes, and endfeet during SE induction and observed enhanced Ca²⁺ signals in both the somata and perivascular endfeet of astrocytes. We employed genetic knockout of TRPM4 (Trpm4 ^-/- ) and glibenclamide treatment to explore the role of sulfonylurea receptor 1 transient receptor potential melastatin-4 (SUR1-TRPM4) channel in these Ca²⁺ responses. Both approaches significantly suppressed the Ca²⁺ signals in the astrocytic endfeet and reduced perivascular expression of the Ca²⁺-related signaling pathway sensor calmodulin (CaM). Furthermore, we found that AQP4 localization was no longer confined to the domains of astrocytic endfeet following SE. Inhibition of SUR1-TRPM4 through pharmacological blockade or gene deletion restored the subcellular localization of AQP4, reduced cerebral edema, and improved cognitive outcomes post-SE. Our findings suggest that SUR1-TRPM4 plays a pivotal role in regulating astrocytic Ca²⁺ signals and mediating the aberrant expression and subcellular localization of astrocytic AQP4 along perivascular pathways. Together, these findings demonstrate a novel molecular mechanism underscoring SUR1-TRPM4 therapy in the treatment of SE characterized by dysregulated Ca²⁺ signaling in astrocytic endfeet.

Astrocytes swell in response to elevations in extracellular K⁺ concentration. This K⁺-induced swelling is widely believed to be due to astrocytic K⁺ uptake, even if the underlying mechanisms are not fully understood. Conflicting results pertaining to the role of the brain water channel AQP4 in K⁺-induced swelling have been presented. This calls for revisiting the effect of AQP4 on K⁺-induced astrocytic swelling dynamics. In this study, we performed two-photon microscopy of acute hippocampal slices from wildtype (WT) and Aqp4 ^−/− mice to assess astrocytic swelling in response to medium high 10 mM and pathologically high 50 mM [K⁺] solutions. We demonstrate that K⁺-induced swelling is attenuated in Aqp4 ^−/− astrocytes exposed to 10 mM [K⁺]_o compared to WT. In slices exposed to 50 mM [K⁺]_o, peak swelling was similar between the two genotypes, whereas the cell volume recovery was more complete in Aqp4 ^−/− astrocytes. We demonstrate that the two [K⁺] concentrations elicit fundamentally different astrocytic Ca²⁺ signaling responses, and that the Ca²⁺ signaling response differs between the genotypes in the 10 mM [K⁺]_o scenario. Our findings suggest that K⁺-induced astrocytic swelling has different mechanistic underpinnings, depending on the K⁺ concentration to which the astrocytes are exposed, and that altered astrocytic Ca²⁺ signaling is a putative mechanism involved.

Neuroinflammation, particularly astrocyte reactivity, is increasingly linked to schizophrenia (SCZ). Yet, the crosstalk between astrocytes and microglia in SCZ, especially under pro-inflammatory conditions, remains unclear. Here, we employed human induced-pluripotent stem cells to compare how astrocytes from five age-matched individuals with SCZ and five neurotypical controls, upon stimulation with TNF-α, affected microglial biology. TNF-α stimulation of SCZ astrocytes, relative to their control counterparts, triggered increased mRNA expression of pro-inflammatory cytokines and CX3CL1. Interestingly, transcriptomic and gene set enrichment analyses revealed that reactive SCZ astrocytes promoted the downregulation of biological processes associated with immune cell proliferation and activation, phagocytosis, and cell migration in induced microglial-like cells (iMGs). Under such conditions, iMGs assumed a dystrophic/senescent-like phenotype, which was associated with accelerated transcriptional aging. Functional validations showed that TNF-α-stimulated SCZ astrocytes promoted reduced synaptoneurosomes phagocytosis by iMGs. Interestingly, while both reactive control and SCZ astrocytes were capable of inducing significant microglial migration in a CX3CR1-dependent manner, TNF-α-stimulated SCZ astrocytes failed to promote greater iMG chemotaxis, compared with their stimulated control counterparts, despite secreting more than twice as much CX3CL1. This was likely due to SCZ astrocytes triggering reduction in CX3CR1 plasma membrane levels in iMGs. Altogether, these findings suggest that astrocytes contribute to SCZ pathology by altering normal microglial function and inducing a dystrophic phenotype.

Cover Illustration: Oligodendrocyte binds to laminin on the perivascular basement membrane in the murine cortex at the age of postnatal day 16 (red: CC-1; green: laminin alpha-2; blue: DAPI). (See Sasaki, B., et al, https://doi.org/10.1002/glia.70027)