Glia最新文献

Experiments to study the biology of addiction have historically focused on the mechanisms through which drugs of abuse drive changes in the functioning of neurons and neural circuits. Glia have often been ignored in these studies, however, and this has left many questions in the field unanswered, particularly, surrounding how glia contribute to changes in synaptic plasticity, regulation of neuroinflammation, and functioning of neural ensembles given massive changes in signaling across the CNS. Omics methods (transcriptomics, translatomics, epigenomics, proteomics, metabolomics, and others) have expanded researchers' abilities to generate hypotheses and carry out mechanistic studies of glial cells during acquisition of drug taking, intoxication, withdrawal, and relapse to drug seeking. Here, we present a survey of how omics technological advances are revising our understanding of astrocytes, microglia, oligodendrocytes, and ependymal cells in addiction biology.

Astrocytes in the cerebrum play important roles such as the regulation of synaptic functions, homeostasis, water transport, and the blood–brain barrier. It has been proposed that astrocytes in the cerebrum acquired diversity and developed functionally during evolution. Here, we show that like human astrocytes, ferret astrocytes in the cerebrum exhibit various morphological subtypes which mice do not have. We found that layer 1 of the ferret cerebrum contained not only protoplasmic astrocytes but also pial interlaminar astrocytes and subpial interlaminar astrocytes. Morphologically polarized astrocytes, which have a long unbranched process, were found in layer 6. Like human white matter, ferret white matter exhibited four subtypes of astrocytes. Furthermore, our quantification showed that ferret astrocytes had a larger territory size and a longer radius length than mouse astrocytes. Thus, our results indicate that, similar to the human cerebrum, the ferret cerebrum has a well-developed diversity of astrocytes. Ferrets should be useful for investigating the molecular and cellular mechanisms leading to astrocyte diversity, the functions of each astrocyte subtype and the involvement of different astrocyte subtypes in various neurological diseases.

Astrocytes play an essential role in regulating synaptic transmission. This study describes a novel form of modulation of excitatory synaptic transmission in the mouse hippocampus by astrocytic G-protein-coupled receptors (GPCRs). We have previously described astrocytic glutamate release via protease-activated receptor-1 (PAR1) activation, although the regulatory mechanisms for this are complex. Through electrophysiological analysis and modeling, we discovered that PAR1 activation consistently increases the concentration and duration of glutamate in the synaptic cleft. This effect was not due to changes in the presynaptic glutamate release or alteration in glutamate transporter expression. However, blocking group II metabotropic glutamate receptors (mGluR2/3) abolished PAR1-mediated regulation of synaptic glutamate concentration, suggesting a role for this GPCR in mediating the effects of PAR1 activation on glutamate release. Furthermore, activation of mGluR2/3 causes glutamate release through the TREK-1 channel in hippocampal astrocytes. These data show that astrocytic GPCRs engage in a novel regulatory mechanism to shape the time course of synaptically-released glutamate in excitatory synapses of the hippocampus.

The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP) levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. As CKB and the creatine-phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early-stage energy deficits in AD.

Cholesterol is crucial for the proper functioning of eukaryotic cells, especially neurons, which rely on cholesterol to maintain their complex structure and facilitate synaptic transmission. However, brain cells are isolated from peripheral cholesterol by the blood–brain barrier and mature neurons primarily uptake the cholesterol synthesized by astrocytes for proper function. This study aimed to investigate the effect of aging on cholesterol trafficking in astrocytes and its delivery to neurons. We found that aged astrocytes accumulated high levels of cholesterol in the lysosomal compartment, and this cholesterol buildup can be attributed to the simultaneous occurrence of two events: decreased levels of the ABCA1 transporter, which impairs ApoE-cholesterol export from astrocytes, and reduced expression of NPC1, which hinders cholesterol release from lysosomes. We show that these two events are accompanied by increased microR-33 in aged astrocytes, which targets ABCA1 and NPC1. In addition, we demonstrate that the microR-33 increase is triggered by oxidative stress, one of the hallmarks of aging. By coculture experiments, we show that cholesterol accumulation in astrocytes impairs the cholesterol delivery from astrocytes to neurons. Remarkably, we found that this altered transport of cholesterol could be alleviated through treatment with endocannabinoids as well as cannabidiol or CBD. Finally, according to data demonstrating that aged astrocytes develop an A1 phenotype, we found that cholesterol buildup is also observed in reactive C3+ astrocytes. Given that reduced neuronal cholesterol affects synaptic plasticity, the ability of cannabinoids to restore cholesterol transport from aged astrocytes to neurons holds significant implications in aging and inflammation.

Most excitatory synapses in the mammalian brain are contacted or ensheathed by astrocyte processes, forming tripartite synapses. Astrocytes are thought to be critical regulators of the structural and functional dynamics of synapses. While the degree of synaptic coverage by astrocytes is known to vary across brain regions and animal species, the reason for and implications of this variability remains unknown. Further, how astrocyte coverage of synapses relates to in vivo functional properties of individual synapses has not been investigated. Here, we characterized astrocyte coverage of synapses of pyramidal neurons in the ferret visual cortex and, using correlative light and electron microscopy, examined their relationship to synaptic strength and sensory-evoked Ca²⁺ activity. Nearly, all synapses were contacted by astrocytes, and most were contacted along the axon–spine interface. Structurally, we found that the degree of synaptic astrocyte coverage directly scaled with synapse size and postsynaptic density complexity. Functionally, we found that the amount of astrocyte coverage scaled with how selectively a synapse responds to a particular visual stimulus and, at least for the largest synapses, scaled with the reliability of visual stimuli to evoke postsynaptic Ca²⁺ events. Our study shows astrocyte coverage is highly correlated with structural metrics of synaptic strength of excitatory synapses in the visual cortex and demonstrates a previously unknown relationship between astrocyte coverage and reliable sensory activation.

Astrocytes that reside in superficial (SL) and deep cortical layers have distinct molecular profiles and morphologies, which may underlie specific functions. Here, we demonstrate that the production of SL and deep layer (DL) astrocyte populations from neural progenitor cells in the mouse is temporally regulated. Lineage tracking following in utero and postnatal electroporation with PiggyBac (PB) EGFP and birth dating with EdU and FlashTag, showed that apical progenitors produce astrocytes during late embryogenesis (E16.5) that are biased to the SL, while postnatally labeled (P0) astrocytes are biased to the DL. In contrast, astrocytes born during the predominantly neurogenic window (E14.5) showed a random distribution in the SL and DL. Of interest, E13.5 astrocytes birth dated at E13.5 with EdU showed a lower layer bias, while FT labeling of apical progenitors showed no bias. Finally, examination of the morphologies of “biased” E16.5- and P0-labeled astrocytes demonstrated that E16.5-labeled astrocytes exhibit different morphologies in different layers, while P0-labeled astrocytes do not. Differences based on time of birth are also observed in the molecular profiles of E16.5 versus P0-labeled astrocytes. Altogether, these results suggest that the morphological, molecular, and positional diversity of cortical astrocytes is related to their time of birth from ventricular/subventricular zone progenitors.

The nervous and the immune systems undergo a continuous cross talk, starting from early development and continuing throughout adulthood and aging. Defects in this cross talk contribute to neurodevelopmental and neurodegenerative diseases. Microglia are the resident immune cells in the brain that are primarily involved in this bidirectional communication. Among the microglial genes, trem2 is a key player, controlling the functional state of microglia and being at the forefront of many processes that require interaction between microglia and other brain components, such as neurons and oligodendrocytes. The present review focuses on the early developmental window, describing the early brain processes in which TREM2 is primarily involved, including the modulation of synapse formation and elimination, the control of neuronal bioenergetic states as well as the contribution to myelination processes and neuronal circuit formation. By causing imbalances during these early maturation phases, dysfunctional TREM2 may have a striking impact on the adult brain, making it a more sensitive target for insults occurring during adulthood and aging.

As one of the top causes of blindness worldwide, glaucoma leads to diverse optic neuropathies such as degeneration of retinal ganglion cells (RGCs). It is widely accepted that the level of intraocular pressure (IOP) is a major risk factor in human glaucoma, and reduction of IOP level is the principally most well-known method to prevent cell death of RGCs. However, clinical studies show that lowering IOP fails to prevent RGC degeneration in the progression of glaucoma. Thus, a comprehensive understanding of glaucoma pathological process is required for developing new therapeutic strategies. In this study, we provide functional and histological evidence showing that optic nerve defects occurred before retina damage in an ocular hypertension glaucoma mouse model, in which oligodendroglial lineage cells were responsible for the subsequent neuropathology. By treatment with clemastine, an Food and Drug Administration (FDA)-approved first-generation antihistamine medicine, we demonstrate that the optic nerve and retina damages were attenuated via promoting oligodendrocyte precursor cell (OPC) differentiation and enhancing remyelination. Taken together, our results reveal the timeline of the optic neuropathies in glaucoma and highlight the potential role of oligodendroglial lineage cells playing in its treatment. Clemastine may be used in future clinical applications for demyelination-associated glaucoma.

The adult brain retains a high repopulation capacity of astrocytes after deletion, and both mature astrocytes in the neocortex and neural stem cells in neurogenic regions possess the potential to generate astrocytes. However, the origin and the repopulation dynamics of the repopulating astrocytes after deletion remain largely unclear. The number of astrocytes is reduced in the medial prefrontal cortex (mPFC) of patients with depression, and selective elimination of mPFC astrocytes is sufficient to induce depression-like behaviors in rodents. However, whether astrocyte repopulation capacity is impaired in depression is unknown. In this study, we used different transgenic mouse lines to genetically label different cell types and demonstrated that in the mPFC of normal adult mice of both sexes, mature astrocytes were a major source of the repopulating astrocytes after acute deletion induced by an astrocyte-specific toxin, L-alpha-aminoadipic acid (L-AAA), and astrocyte regeneration was accomplished within two weeks accompanied by reversal of depression-like behaviors. Furthermore, re-ablation of mPFC astrocytes post repopulation led to reappearance of depression-like behaviors. In adult male mice subjected to 14-day chronic restraint stress, a well-validated mouse model of depression, the number of mPFC astrocytes was reduced; however, the ability of mPFC astrocytes to repopulate after L-AAA-induced deletion was largely unaltered. Our study highlights a potentially beneficial role for repopulating astrocytes in depression and provides novel therapeutic insights into enhancing local mature astrocyte generation in depression.