Glial Signals Research Articles

Aqueous Humor Cytokines in Idiopathic Epiretinal Membrane: Correlation with Disease Severity.

To analyze the concentration of aqueous humor (AH) cytokines in eyes with idiopathic epiretinal membrane (iERM) and to investigate their potential correlation with disease severity. Retrospective cross-sectional case-control institutional study. A total of 16 eyes of 16 iERM patients and 14 eyes of 14 age-matched healthy controls were enrolled. AH samples were analyzed for various biomarkers using a glass-chip protein array. Cytokines associated with inflammation, fibrosis, angiogenesis, and glial signal transduction were quantified. Significant differences in cytokine concentration were observed between the iERM group and controls, with 19 cytokines elevated in the iERM group (among them IL-6, IL-8, PDGF-AB, PDGF-BB, TGFB-1, TGFB-2, TGFB-3, VEGF A, VEGF C, VEGF D, p < 0,05, 95% confidence interval). Correlation analysis revealed associations between cytokine levels and iERM severity. Notably, stages 2, 3, and 4 of iERM demonstrated increased levels of various biomarkers. This study provides insights into the complex molecular interactions underlying iERM pathogenesis, describing a correlation between neuroinflammation and iERM severity.

PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice.

We have generated using CRISPR/Cas9 technology a partially humanized mouse model of the neurometabolic disease phenylketonuria (PKU), carrying the highly prevalent PAH variant c.1066-11G>A. This variant creates an alternative 3' splice site, leading to the inclusion of 9 nucleotides coding for 3 extra amino acids between Q355 and Y356 of the protein. Homozygous Pah c.1066-11A mice, with a partially humanized intron 10 sequence with the variant, accurately recapitulate the splicing defect and present almost undetectable hepatic PAH activity. They exhibit fur hypopigmentation, lower brain and body weight and reduced survival. Blood and brain phenylalanine levels are elevated, along with decreased tyrosine, tryptophan and monoamine neurotransmitter levels. They present behavioral deficits, mainly hypoactivity and diminished social interaction, locomotor deficiencies and an abnormal hind-limb clasping reflex. Changes in the morphology of glial cells, increased GFAP and Iba1 staining signals and decreased myelinization are observed. Hepatic tissue exhibits nearly absent PAH protein, reduced levels of chaperones DNAJC12 and HSP70 and increased autophagy markers LAMP1 and LC3BII, suggesting possible coaggregation of mutant PAH with chaperones and subsequent autophagy processing. This PKU mouse model with a prevalent human variant represents a useful tool for pathophysiology research and for novel therapies development.

Regulation of enolase activation to promote neural protection and regeneration in spinal cord injury.

Spinal cord injury (SCI) is a debilitating condition characterized by damage to the spinal cord resulting in loss of function, mobility, and sensation with no U.S. Food and Drug Administration-approved cure. Enolase, a multifunctional glycolytic enzyme upregulated after SCI, promotes pro- and anti-inflammatory events and regulates functional recovery in SCI. Enolase is normally expressed in the cytosol, but the expression is upregulated at the cell surface following cellular injury, promoting glial cell activation and signal transduction pathway activation. SCI-induced microglia activation triggers pro-inflammatory mediators at the injury site, activating other immune cells and metabolic events, i.e., Rho-associated kinase, contributing to the neuroinflammation found in SCI. Enolase surface expression also activates cathepsin X, resulting in cleavage of the C-terminal end of neuron-specific enolase (NSE) and non-neuronal enolase (NNE). Fully functional enolase is necessary as NSE/NNE C-terminal proteins activate many neurotrophic processes, i.e., the plasminogen activation system, phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B, and mitogen-activated protein kinase/extracellular signal-regulated kinase. Studies here suggest an enolase inhibitor, ENOblock, attenuates the activation of Rho-associated kinase, which may decrease glial cell activation and promote functional recovery following SCI. Also, ENOblock inhibits cathepsin X, which may help prevent the cleavage of the neurotrophic C-terminal protein allowing full plasminogen activation and phosphatidylinositol-4,5-bisphosphate 3-kinase/mitogen-activated protein kinase activity. The combined NSE/cathepsin X inhibition may serve as a potential therapeutic strategy for preventing neuroinflammation/degeneration and promoting neural cell regeneration and recovery following SCI. The role of cell membrane-expressed enolase and associated metabolic events should be investigated to determine if the same strategies can be applied to other neurodegenerative diseases. Hence, this review discusses the importance of enolase activation and inhibition as a potential therapeutic target following SCI to promote neuronal survival and regeneration.

Differentiation signals from glia are fine-tuned to set neuronal numbers during development.

Neural circuit formation and function require that diverse neurons are specified in appropriate numbers. Known strategies for controlling neuronal numbers involve regulating either cell proliferation or survival. We used the Drosophila visual system to probe how neuronal numbers are set. Photoreceptors from the eye-disc induce their target field, the lamina, such that for every unit eye there is a corresponding lamina unit (column). Although each column initially contains ~6 post-mitotic lamina precursors, only 5 differentiate into neurons, called L1-L5; the 'extra' precursor, which is invariantly positioned above the L5 neuron in each column, undergoes apoptosis. Here, we showed that a glial population called the outer chiasm giant glia (xgO), which resides below the lamina, secretes multiple ligands to induce L5 differentiation in response to epidermal growth factor (EGF) from photoreceptors. By forcing neuronal differentiation in the lamina, we uncovered that though fated to die, the 'extra' precursor is specified as an L5. Therefore, two precursors are specified as L5s but only one differentiates during normal development. We found that the row of precursors nearest to xgO differentiate into L5s and, in turn, antagonise differentiation signalling to prevent the 'extra' precursors from differentiating, resulting in their death. Thus, an intricate interplay of glial signals and feedback from differentiating neurons defines an invariant and stereotyped pattern of neuronal differentiation and programmed cell death to ensure that lamina columns each contain exactly one L5 neuron.

Effect and Mechanism of Endothelin Receptor A Inhibitor BQ-123 Combined with Electroacupuncture on Tibia Cancer Pain in Rats.

Objective To research the impact and mechanism of endothelin receptor A inhibitor BQ-123 combined with electroacupuncture on tibia cancer pain in rats. Methods Sprague-Dawley (SD) rats were randomly divided into sham group (SHAM group) and bone cancer pain model group (BCP group). The behavior of SD rats was measured. The histology of the right tibia was observed by hematoxylin-eosin (HE) staining. The remaining rats were randomly divided into model, BQ-123, electroacupuncture, and BQ-123+ electroacupuncture group. Behavioral tests were performed, and mechanical pain threshold (MWT) and thermal pain threshold (TWL) were measured. The expressions of α-smooth muscle actin (αSMA), ETAR (endothelin A receptor), ETB (End of Transmission Block), P-Phosphatidylinositol 3-kinase (PI3K), and P-Protein kinase B (Akt) were detected by real-time fluorescence quantitative PCR and western blot. Results In the BCP group, bone structure was severely damaged, local tissue swelling was obvious, bone trabecula was missing, and bone cortex was discontinuous. The optical density of Glial fibrillary acidic protein (GFAP) and CD11b immunoreactive signal in BCP group was significantly increased, and most of the ETAR of endothelin receptor was comapped with NeuN, and a small part of GFAP was comapped with CD11b, but no comapped with CD11b. The AS score of BQ-123+ electroacupuncture group was significantly lower than that of BQ-123 group and electroacupuncture group (P < 0.05), whereas the MWT and TWL values were significantly higher than that of the BQ-123 group and electroacupuncture group (P < 0.05). The mRNA expression of α-SMA and ETAR in BQ-123+ electroacupuncture group was lower than that in BQ-123 and electroacupuncture group, and the protein expression of P-PI3K and P-Akt in BQ-123+ electroacupuncture group was lower as well. Conclusion BQ-123 may inhibit the activation of PI3K/Akt signal path combined with electroacupuncture to alleviate the effects of tibia cancer pain in rats.

Glial Purinergic Signals and Psychiatric Disorders

Emotion-related neural networks are regulated in part by the activity of glial cells, and glial dysfunction can be directly related to emotional diseases such as depression. Here, we discuss three different therapeutic strategies involving astrocytes that are effective for treating depression. First, the antidepressant, fluoxetine, acts on astrocytes and increases exocytosis of ATP. This has therapeutic effects via brain-derived neurotrophic factor-dependent mechanisms. Second, electroconvulsive therapy is a well-known treatment for drug-resistant depression. Electroconvulsive therapy releases ATP from astrocytes to induce leukemia inhibitory factors and fibroblast growth factor 2, which leads to antidepressive actions. Finally, sleep deprivation therapy is well-known to cause antidepressive effects. Sleep deprivation also increases release of ATP, whose metabolite, adenosine, has antidepressive effects. These independent treatments share the same mechanism, i.e., ATP release from astrocytes, indicating an essential role of glial purinergic signals in the pathogenesis of depression.

Effect of intrathecal administration of exogenous noggin on neuropathic pain.

To explore the effect of intrathecal administration of exogenous noggin (NOG) on the pain behavior in the neuropathic pain (NP) rats through L5 spinal nerve ligation (SNL), and to examine the regulative role of NOG in astrocyte activation, inflammatory cytokines and downstream signals. A total of 40 adult male Sprague Dawley (SD) rats were randomly divided into 3 groups: a control group (n=10), a SNL group (SNL+intrathecal injection of artificial cerebrospinal fluid, n=15), and a SNL+NOG group (SNL+intrathecal injection of recombinant NOG protein, n=15). Von-Frey filaments were used to test the changes of paw withdrawal threshold (PWT) at Day 1 before operation, and Day 1, Day 4, Day 7 and Day 14 after operation in each group. Immunofluorescence was used to observe the activation of astrocyte located in the dorsal horn of spinal cord in the 3 groups. Western blotting was conducted to detect the expression levels of glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), signal transducer and activator of transcription (STAT3) and phosphorylation STAT3 (p-STAT3). Compared with the control group, the PWT in the SNL group was markedly decreased at each time point, together with the increase in GFAP, IL-6 and the ratio of p-STAT3/STAT3 (all P<0.05). Meanwhile, compared with the SNL group, the PWT in the lumbar swelling of spinal cord in the SNL+NOG group was elevated at Day 4 and lasted to Day 14 (P<0.05), accompanied by the decrease in GFAP, IL-6 and the ratio of p-STAT3/STAT3 (all P<0.05). The intrathecal administration of NOG may alleviate NP in the SNL rats through inhibiting astrocyte activation and down-regulating the STAT3 signal pathway.

Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction

Amyloidogenicity and vascular dysfunction are the key players in the pathogenesis of Alzheimer’s disease (AD), involving dysregulated cellular interactions. An intricate balance between neurons, astrocytes, microglia, oligodendrocytes and vascular cells sustains the normal neuronal circuits. Conversely, cerebrovascular diseases overlap neuropathologically with AD, and glial dyshomeostasis promotes AD-associated neurodegenerative cascade. While pathological hallmarks of AD primarily include amyloid-β (Aβ) plaques and neurofibrillary tangles, microvascular disorders, altered cerebral blood flow (CBF), and blood-brain barrier (BBB) permeability induce neuronal loss and synaptic atrophy. Accordingly, microglia-mediated inflammation and astrogliosis disrupt the homeostasis of the neuro-vascular unit and stimulate infiltration of circulating leukocytes into the brain. Large-scale genetic and epidemiological studies demonstrate a critical role of cellular crosstalk for altered immune response, metabolism, and vasculature in AD. The glia associated genetic risk factors include APOE, TREM2, CD33, PGRN, CR1, and NLRP3, which correlate with the deposition and altered phagocytosis of Aβ. Moreover, aging-dependent downregulation of astrocyte and microglial Aβ-degrading enzymes limits the neurotrophic and neurogenic role of glial cells and inhibits lysosomal degradation and clearance of Aβ. Microglial cells secrete IGF-1, and neurons show a reduced responsiveness to the neurotrophic IGF-1R/IRS-2/PI3K signaling pathway, generating amyloidogenic and vascular dyshomeostasis in AD. Glial signals connect to neural stem cells, and a shift in glial phenotype over the AD trajectory even affects adult neurogenesis and the neurovascular niche. Overall, the current review informs about the interaction of neuronal and glial cell types in AD pathogenesis and its critical association with cerebrovascular dysfunction.

Shedding plasma membrane vesicles induced by graphene oxide nanoflakes in brain cultured astrocytes

Microvesicles (MVs) generated and released by astrocytes, the brain prevalent cells, crucially contribute to intercellular communication, representing key vectorized systems able to spread and actively transfer signaling molecules from astrocytes to neurons, ultimately modulating target cell functions. The increasing clinical relevance of these signaling systems requires a deeper understanding of MV features, currently limited by both their nanoscale dimensions and the low rate of their constituent release. Hence, to investigate the features of such glial signals, nanotechnology-based approaches and the applications of unconventional, cost-effective tools in generating MVs are needed. Here, small graphene oxide (s-GO) nanoflakes are used to boost MVs shedding from astrocytes in cultures and s-GO generated MVs are compared with those generated by a natural stimulant, namely ATP, by atomic force microscopy, light scattering, attenuated total reflection–fourier transform infra-red and ultraviolet resonance Raman spectroscopy. We also report the ability of both types of MVs, upon acute and transient exposure of patch clamped cultured neurons, to modulate basal synaptic transmission, inducing a stable increase in synaptic activity accompanied by changes in neuronal plasma membrane elastic features.

Dysfucntion of glial purinergic signals anddepression

Dysfucntion of glial purinergic signals anddepression

Platelet-rich plasma improves chronic inflammatory pain by inhibiting PKM2-mediated aerobic glycolysis in astrocytes.

BackgroundAstrocytes are highly glycolytic cells that play a crucial role in chronic pain. Recently it has been found that inflammation and metabolism are related to the inflammatory stimuli closely that cause cellular metabolic changes. Pyruvate kinase M2 (PKM2) is a critical metabolic kinase in aerobic glycolysis or the Warburg effect. Besides, it also plays a crucial role in cell proliferation and signal transduction, but its role in astrocytes is still unclear.MethodsThe chronic inflammatory pain model was set up by intraplantar injection of complete Freund’s adjuvant (CFA) in Sprague Dawley (SD) rats as well as the cell model was constructed by lipopolysaccharide-treated primary astrocytes. Von Frey filament stimulation was used to continuously observe the changes of pain behavior in rats after modeling. Then, immunofluorescence staining and Western blot tests were used to observe the expression levels of glial fibrillary acidic protein (GFAP), pyruvate kinase (PKM2), signal transducers and activators of transcription 3 (STAT3) and high mobility group box-1 protein (HMGB1). After that, specific kits measured lactate contents. Finally, we observed the platelet-rich plasma’s (PRP) effect on mechanical hyperalgesia in rats with inflammatory pain induced by CFA and its effect on related signal molecules.ResultsWe found that in the CFA-induced inflammatory pain model, astrocytes were significantly activated, GFAP was increased, PKM2 was significantly up-regulated, and the glycolytic product lactate was increased. Also, intrathecal injection of PRP increased the pain threshold, inhibited the activation of astrocytes, and decreased the expression of PKM2 and aerobic glycolysis; in LPS-activated primary astrocytes as an in vitro model, we found PKM2 translocation activationSTAT3 signaling resulted in sustained activation of astrocyte marker GFAP, and the expression level and localization of p-STAT3 were correlated with PKM2. PRP could inhibit the activation of astrocytes, reduce the expression of PKM2 and the expression levels of glycolysis and GFAP, GLUT1, and p-STAT3 in astrocytes.ConclusionsOur findings suggest PKM2 not only plays a glycolytic role in astrocytes, but also plays a crucial role in astrocyte-activated signaling pathways, and PRP attenuates CFA induced inflammatory pain by inhibiting aerobic glycolysis in astrocytes, providing a new therapeutic target for the treatment of inflammatory pain.

EZcalcium: Open-Source Toolbox for Analysis of Calcium Imaging Data.

Fluorescence calcium imaging using a range of microscopy approaches, such as two-photon excitation or head-mounted “miniscopes,” is one of the preferred methods to record neuronal activity and glial signals in various experimental settings, including acute brain slices, brain organoids, and behaving animals. Because changes in the fluorescence intensity of genetically encoded or chemical calcium indicators correlate with action potential firing in neurons, data analysis is based on inferring such spiking from changes in pixel intensity values across time within different regions of interest. However, the algorithms necessary to extract biologically relevant information from these fluorescent signals are complex and require significant expertise in programming to develop robust analysis pipelines. For decades, the only way to perform these analyses was for individual laboratories to write their custom code. These routines were typically not well annotated and lacked intuitive graphical user interfaces (GUIs), which made it difficult for scientists in other laboratories to adopt them. Although the panorama is changing with recent tools like CaImAn, Suite2P, and others, there is still a barrier for many laboratories to adopt these packages, especially for potential users without sophisticated programming skills. As two-photon microscopes are becoming increasingly affordable, the bottleneck is no longer the hardware, but the software used to analyze the calcium data optimally and consistently across different groups. We addressed this unmet need by incorporating recent software solutions, namely NoRMCorre and CaImAn, for motion correction, segmentation, signal extraction, and deconvolution of calcium imaging data into an open-source, easy to use, GUI-based, intuitive and automated data analysis software package, which we named EZcalcium.

A proteolytic C-terminal fragment of Nogo-A (reticulon-4A) is released in exosomes and potently inhibits axon regeneration

Glial signals are known to inhibit axonal regeneration and functional recovery after mammalian central nervous system trauma, including spinal cord injury. Such signals include membrane-associated proteins of the oligodendrocyte plasma membrane and astrocyte-derived, matrix-associated proteins. Here, using cell lines and primary cortical neuron cultures, recombinant protein expression, immunoprecipitation and immunoblot assays, transmission EM of exosomes, and axon regeneration assays, we explored the secretion and activity of the myelin-associated neurite outgrowth inhibitor Nogo-A and observed exosomal release of a 24-kDa C-terminal Nogo-A fragment from cultured cells. We found that the cleavage site in this 1192-amino-acid-long fragment is located between amino acids 961-971. We also detected a Nogo-66 receptor (NgR1)-interacting Nogo-66 domain on the exosome surface. Enzyme inhibitor treatment and siRNA knockdown revealed that β-secretase 1 (BACE1) is the protease responsible for Nogo-A cleavage. Functionally, exosomes with the Nogo-66 domain on their surface potently inhibited axonal regeneration of mechanically injured cerebral cortex neurons from mice. Production of this fragment was observed in the exosomal fraction from neuronal tissue lysates after spinal cord crush injury of mice. We also noted that, relative to the exosomal marker Alix, a Nogo-immunoreactive, 24-kDa protein is enriched in exosomes 2-fold after injury. We conclude that membrane-associated Nogo-A produced in oligodendrocytes is processed proteolytically by BACE1, is released via exosomes, and is a potent diffusible inhibitor of regenerative growth in NgR1-expressing axons.

Glia Promote Synaptogenesis through an IQGAP PES-7 in C. elegans

Synapses are fundamental to the normal function of the nervous system. Glia play a pivotal role in regulating synaptic formation. However, how presynaptic neurons assemble synaptic structure in response to the glial signals remains largely unexplored. To address this question, we use cima-1 mutant C.elegans as an invivo model, in which the astrocyte-like VCSC glial processes ectopically reach an asynaptic neurite region and promote presynaptic formation there. Through an RNAi screen, we find that the Rho GTPase CDC-42 and IQGAP PES-7 are required in presynaptic neurons for VCSC glia-induced presynaptic formation. In addition, we find that cdc-42 and pes-7 are also required for normal synaptogenesis during postembryonic developmental stages. PES-7 activated by CDC-42 promotes presynaptic formation, most likely through regulating F-actin assembly. Given the evolutionary conservation of CDC-42 and IQGAPs, we speculate that our findings in C.elegans apply to vertebrates.

Glia Promote Synaptogenesis Through IQGAP

Synapses are fundamental to the normal functioning of the nervous system. Glia play a pivotal role in regulating synaptic formation. However, how presynaptic neurons assemble synaptic structure in response to the glial signals remains largely unexplored. To address this question, we use cima-1 mutant C. elegans as an in vivo model, in which the VCSC glial processes contact to the ectopic neurite region and thereby promoting the ectopic synapse formation at adult stage. Through RNAi screen, we found that presynaptic Rho GTPase CDC-42 and IQGAP PES-7 are required for VCSC glia-induced synaptic formation. Additionally, we found that cdc-42 and pes-7 are only required but also sufficient for normal synaptogenesis during postembryonic developmental stages. Mechanistically, the glia-neurite contact sites, PES-7 activated by CDC-42 promotes presynaptic formation through regulating F-actin assembly. Our data provide new insights into the molecular mechanisms by which presynaptic neurons assemble synaptic structures in response to synaptogenesis signals from glia during post embryonic development. Our results indicate that CDC-42 and PES-7 play critical roles in the temporal regulation of synaptic spatial specificity. Given the evolutionary conservation of CDC-42 and IQGAPs, we speculate that our findings in C. elegans apply to vertebrates.

Role of glia in prefrontal white matter abnormalities in first episode psychosis or mania detected by diffusion tensor spectroscopy

BackgroundWhite matter (WM) abnormalities are amongst the most commonly described neuroimaging findings in patients with psychotic disorders including schizophrenia (SZ) and bipolar disorder (BD), and may be central to pathophysiology. Few studies have directly compared WM abnormalities in patients with SZ and BD in the first episode of illness, and no studies to date have attempted to separate abnormalities of axon and myelin using complementary MRI techniques. MethodsWe examined WM abnormalities in young adults with SZ (n = 19) or BD (n = 16) within the first year of illness onset, and healthy controls (n = 22) using a combination of diffusion tensor spectroscopy to measure NAA, creatine (Cr), and choline (Cho), and magnetization transfer ratio (MTR). MTR reflects myelin content, NAA diffusion is neuron specific, and Cr and Cho diffusion reflect both neuron and glial signal. ResultsWe found no differences in MTR or NAA ADC in either patient group compared to controls, but significant elevations of both Cr and Cho diffusion in patients with SZ, and elevations of Cho diffusion in patients with BD. Elevations in Cr and Cho diffusion in the absence of NAA diffusion abnormalities indicate that the aberrant signal arises in glia. ConclusionsGlial abnormalities were present and detectable by the first episode of psychosis, whereas major abnormalities in axon and myelin were not. Examination of these neurobiological markers early in the course of illness may clarify the neuroprogressive nature of these distinct aspects of WM, and their associations with early clinical phenotypes.

Review of the Literature on Current Changes in the Timing of Pubertal Development and the Incomplete Forms of Early Puberty.

Puberty is a sensitive period of life characterized by the appearance of secondary sex characteristics which leads to a complete sexual maturation. It physiologically starts between the age of 8 and 13 years in girls and 9 and 14 years in boys. In the last two decades, several studies have showed that start of puberty has moved up to younger ages by 12–18 months, and some of the hypotheses trying to explain this change include the role of nutritional status and obesity and the influence of extrinsic factors such as exposure to endocrine-disrupting chemicals (EDCs), as well. The hypothalamic–hypophysis–gonadal axis develops during embryogenesis, and except for a period of activation immediately after birth, remains suppressed until the onset of pubertal development. At the beginning of puberty, the pulse generator is reactivated, probably due to progressive stimulatory influences on GnRH neurons from glial signals and neurotrasmitters. Kisspeptin and its receptor play a fundamental role in this phase. Premature Pubarche/Adrenarche, Premature Thelarche, and Premature Menarche are incomplete forms of precocious pubertal development that have their origin in endocrine mechanisms that only recently have started to be understood. It is important to distinguish these forms from the complete ones in order to reassure patients and parents about the non-evolution of pubertal progression and avoid non-useful treatments with analogous LHRH.

Oligodendroglial Lineage Cells in Thyroid Hormone-Deprived Conditions.

Oligodendrocytes are supporting glial cells that ensure the metabolism and homeostasis of neurons with specific synaptic axoglial interactions in the central nervous system. These require key myelinating glial trophic signals important for growth and metabolism. Thyroid hormone (TH) is one such trophic signal that regulates oligodendrocyte maturation, myelination, and oligodendroglial synaptic dynamics via either genomic or nongenomic pathways. The intracellular and extracellular transport of TH is facilitated by a specific transmembrane transporter known as the monocarboxylate transporter 8 (MCT8). Dysfunction of the MCT8 due to mutation, inhibition, or downregulation during brain development leads to inherited hypomyelination, which manifests as psychomotor retardation in the X-linked inherited Allan-Herndon-Dudley syndrome (AHDS). In particular, oligodendroglial-specific MCT8 deficiency may restrict the intracellular T3 availability, culminating in deficient metabolic communication between the oligodendrocytes and the neurons they ensheath, potentially promulgating neurodegenerative adult diseases such as multiple sclerosis (MS). Based on the therapeutic effects exhibited by TH in various preclinical studies, particularly related to its remyelinating potential, TH has now entered the initial stages of a clinical trial to test the therapeutic efficacy in relapsing-remitting MS patients (NCT02506751). However, TH analogs, such as DITPA or Triac, may well serve as future therapeutic options to rescue mature oligodendrocytes and/or promote oligodendrocyte precursor cell differentiation in an environment of MCT8 deficiency within the CNS. This review outlines the therapeutic strategies to overcome the differentiation blockade of oligodendrocyte precursors and maintain mature axoglial interactions in TH-deprived conditions.

Glial purinergic signals as a target for antidepressants

Glial purinergic signals as a target for antidepressants

Action Potential Firing Induces Sodium Transients in Macroglial Cells of the Mouse Corpus Callosum

Recent work has established that glutamatergic synaptic activity induces transient sodium elevations in grey matter astrocytes by stimulating glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST). Glial sodium transients have diverse functional consequences but are largely unexplored in white matter. Here, we employed ratiometric imaging to analyse sodium signalling in macroglial cells of mouse corpus callosum. Electrical stimulation resulted in robust sodium transients in astrocytes, oligodendrocytes and NG2 glia, which were blocked by tetrodotoxin, demonstrating their dependence on axonal action potentials (APs). Action potential-induced sodium increases were strongly reduced by combined inhibition of ionotropic glutamate receptors and glutamate transporters, indicating that they are related to release of glutamate. While AMPA receptors were involved in sodium influx into all cell types, oligodendrocytes and NG2 glia showed an additional contribution of NMDA receptors. The transporter subtypes GLT-1 and GLAST were detected at the protein level and contributed to glutamate-induced glial sodium signals, indicating that both are functionally relevant for glutamate clearance in corpus callosum. In summary, our results demonstrate that white matter macroglial cells experience sodium influx through ionotropic glutamate receptors and glutamate uptake upon AP generation. Activity-induced glial sodium signalling may thus contribute to the communication between active axons and macroglial cells.