Glial Types Research Articles

Astrocyte regional specialization is shaped by postnatal development.

Astrocytes are an abundant class of glial cells with critical roles in neural circuit assembly and function. Though many studies have uncovered significant molecular distinctions between astrocytes from different brain regions, how this regionalization unfolds over development is not fully understood. We used single-nucleus RNA sequencing to characterize the molecular diversity of brain cells across six developmental stages and four brain regions in the mouse and marmoset brain. Our analysis of over 170,000 single astrocyte nuclei revealed striking regional heterogeneity among astrocytes, particularly between telencephalic and diencephalic regions, at all developmental time points surveyed in both species. At the stages sampled, most of the region patterning was private to astrocytes and not shared with neurons or other glial types. Though astrocytes were already regionally patterned in late embryonic stages, this region-specific astrocyte gene expression signature changed dramatically over postnatal development, and its composition suggests that regional astrocytes further specialize postnatally to support their local neuronal circuits. Comparing across species, we found divergence in the expression of astrocytic region- and age-differentially expressed genes and the timing of astrocyte maturation relative to birth between mouse and marmoset, as well as hundreds of species differentially expressed genes. Finally, we used expansion microscopy to show that astrocyte morphology is largely conserved across gray matter forebrain regions in the mouse, despite substantial molecular divergence.

DISP-07. GLIOMAS IN HIV-POSITIVE PATIENTS CAN BE IDH-MUTANT OR -WILDTYPE

Abstract Recent review has emphasized that glioblastoma (GBM) in persons living with human immunodeficiency virus (HIV)(PLWH) is “severely underreported in the literature” (PMID 35857248), since only 24 cases could be identified. This 2022 study concluded that overall survival in this patient group is less than in persons who are HIV-negative. Given the predominantly single-case reports in the literature, it is not surprising that “data remains limited”. To this end, we report our 15-year experience with patients with HIV-positivity diagnosed at our institution. Text word search of Department of Pathology databases, 2008-2023, with review of histological sections and the medical record. 7 patients living with PLWH were identified, all males, ages at diagnosis 44-61 years, median 58 years. 3 had tumors that met histological criteria for GBM, IDH-wildtype, WHO grade 4, 1 had GBM by modern molecular criteria and 2 had astrocytoma, IDH-mutant, WHO grade 4. One of the latter had co-existent diffuse high grade B cell lymphoma intimately admixed within his glioma while the final patient had multifocal brain lesions of different neuroimaging appearances, with the bifrontal tumor consistent with GBM and posterior frontal lesions suspicious for progressive multifocal leukoencephalopathy. At the time of tumor diagnosis, 1 had HIV for 20+ years, a second was well controlled with normal CD4 count and a third had not yet been on anti-retroviral agents. Survival was poor, with 2 PLWH with IDH-mutant tumors succumbing at 2 and 4 months and 3 with GBMs at 7, 12 and 32 months; a 4th is alive at 6 months. PLWH can develop various glial tumor types including both IDH-mutant and IDH-wildtype tumors, strongly suggesting co-incident rather than causal relationship. Tumors may be first diagnosed at varying stages of their immunodeficiency disorder; survival is poor even for PLWH with IDH-mutant grade 4 tumor.

Enteric glia as a player of gut-brain interactions during Parkinson's disease.

The enteric glia has been shown as a potential component of neuroimmune interactions that signal in the gut-brain axis during Parkinson's disease (PD). Enteric glia are a peripheral glial type found in the enteric nervous system (ENS) that, associated with enteric neurons, command various gastrointestinal (GI) functions. They are a unique cell type, with distinct phenotypes and distribution in the gut layers, which establish relevant neuroimmune modulation and regulate neuronal function. Comprehension of enteric glial roles during prodromal and symptomatic phases of PD should be a priority in neurogastroenterology research, as the reactive enteric glial profile, gastrointestinal dysfunction, and colonic inflammation have been verified during the prodromal phase of PD-a moment that may be interesting for interventions. In this review, we explore the mechanisms that should govern enteric glial signaling through the gut-brain axis to understand pathological events and verify the possible windows and pathways for therapeutic intervention. Enteric glia directly modulate several functional aspects of the intestine, such as motility, visceral sensory signaling, and immune polarization, key GI processes found deregulated in patients with PD. The search for glial biomarkers, the investigation of temporal-spatial events involving glial reactivity/signaling, and the proposal of enteric glia-based therapies are clearly demanded for innovative and intestine-related management of PD.

Dynamic Involvement of Striatal NG2-glia in L-DOPA Induced Dyskinesia in Parkinsonian Rats: Effects of Doxycycline.

NG2-glia alters its dynamics in response to L-DOPA-induced dyskinesia. In these animals, striatal NG2-glia density was reduced with cells presenting activated phenotype while doxycycline antidyskinetic therapy promotes a return to NG2-glia cell density and protein to a not activated state.

Oligodendrocyte precursor cells ingest axons in the mouse neocortex

Neurons in the developing brain undergo extensive structural refinement as nascent circuits adopt their mature form. This physical transformation of neurons is facilitated by the engulfment and degradation of axonal branches and synapses by surrounding glial cells, including microglia and astrocytes. However, the small size of phagocytic organelles and the complex, highly ramified morphology of glia have made it difficult to define the contribution of these and other glial cell types to this crucial process. Here, we used large-scale, serial section transmissionelectron microscopy (TEM) with computational volume segmentation to reconstruct the complete 3D morphologies of distinct glial types in the mouse visual cortex, providing unprecedented resolution of their morphology and composition. Unexpectedly, we discovered that the fine processes of oligodendrocyte precursor cells (OPCs), a population of abundant, highly dynamic glial progenitors, frequently surrounded small branches of axons. Numerous phagosomes and phagolysosomes (PLs) containing fragments of axons and vesicular structures were present inside their processes, suggesting that OPCs engage in axon pruning. Single-nucleus RNA sequencing from the developing mouse cortex revealed that OPCs express key phagocytic genes at this stage, as well as neuronal transcripts, consistent with active axon engulfment. Although microglia are thought to be responsible for the majority of synaptic pruning and structural refinement, PLs were ten times more abundant in OPCs than in microglia at this stage, and these structures were markedly less abundant in newly generated oligodendrocytes, suggesting that OPCs contribute substantially to the refinement of neuronal circuits during cortical development.

Analysis of the effectiveness and risk benefit of N acetyl cysteine compared to ceftriaxone in the expression of GLT1 transporters.

The concentration of glutamate in the synaptic cleft is regulated primarily by glutamate transporters, especially by the glial glutamate-specific transporter type 1 (GLT-1). Ceftriaxone (CTX), a β-lactam antibiotic, has been reported to significantly increase GLT-1 expression. N-acetylcysteine ​​as a derivative of cysteine, is oxidized into cystine within the brain, increasing the availability of cystine for the glial cystine-glutamate exchanger, this action increases the amount of glutamate exchanged by glial cells, raising the concentration of glutamate within the extra-synaptic space and effectively promoting GLT-1 transcription. It is suspected that the β-lactam antibiotic ceftriaxone is more effective than N-acetylcysteine ​​in upregulating GLT-1 expression. We conducted a systematic review to investigate the effectiveness of the drugs N-acetylcysteine ​​and ceftriaxone with respect to their effect on increasing the expression of GLT-1 transporters in experimental studies. This systematic review was carried out with methodology in accordance with the Cochrane Handbook and reporting consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The main objective of this work is to determine the difference in effectiveness of N-acetylcysteine compared to Ceftriaxone in the expression of the GLT-1 transporter. A clear superiority is shown by ceftriaxone, because by itself it can induce an increase in the levels of these proteins either in circumstances where the glutamatergic flux is affected or in control groups, in contrast to N-acetylcysteine. which improves the expression of these transporters only when there is a deficit in the levels of GLT-1.

A single-cell transcriptomic atlas of complete insect nervous systems across multiple life stages

Molecular profiles of neurons influence neural development and function but bridging the gap between genes, circuits, and behavior has been very difficult. Here we used single cell RNAseq to generate a complete gene expression atlas of the Drosophila larval central nervous system composed of 131,077 single cells across three developmental stages (1 h, 24 h and 48 h after hatching). We identify 67 distinct cell clusters based on the patterns of gene expression. These include 31 functional mature larval neuron clusters, 1 ring gland cluster, 8 glial clusters, 6 neural precursor clusters, and 13 developing immature adult neuron clusters. Some clusters are present across all stages of larval development, while others are stage specific (such as developing adult neurons). We identify genes that are differentially expressed in each cluster, as well as genes that are differentially expressed at distinct stages of larval life. These differentially expressed genes provide promising candidates for regulating the function of specific neuronal and glial types in the larval nervous system, or the specification and differentiation of adult neurons. The cell transcriptome Atlas of the Drosophila larval nervous system is a valuable resource for developmental biology and systems neuroscience and provides a basis for elucidating how genes regulate neural development and function.

Delta/Notch signaling in glia maintains motor nerve barrier function and synaptic transmission by controlling matrix metalloproteinase expression.

While the role of barrier function in establishing a protective, nutrient-rich, and ionically balanced environment for neurons has been appreciated for some time, little is known about how signaling cues originating in barrier-forming cells participate in maintaining barrier function and influence synaptic activity. We have identified Delta/Notch signaling in subperineurial glia (SPG), a crucial glial type for Drosophila motor axon ensheathment and the blood-brain barrier, to be essential for controlling the expression of matrix metalloproteinase 1 (Mmp1), a major regulator of the extracellular matrix (ECM). Our genetic analysis indicates that Delta/Notch signaling in SPG exerts an inhibitory control on Mmp1 expression. In the absence of this inhibition, abnormally enhanced Mmp1 activity disrupts septate junctions and glial ensheathment of peripheral motor nerves, compromising neurotransmitter release at the neuromuscular junction (NMJ). Temporally controlled and cell type-specific transgenic analysis shows that Delta/Notch signaling inhibits transcription of Mmp1 by inhibiting c-Jun N-terminal kinase (JNK) signaling in SPG. Our results provide a mechanistic insight into the regulation of neuronal health and function via glial-initiated signaling and open a framework for understanding the complex relationship between ECM regulation and the maintenance of barrier function.

The Stem Cell Potential of O-2A Lineage Astroglia

Astrocytes are the most common glial type in the central nervous system. They play pivotal roles in neurophysiological and neuropathological processes. Mounting evidence indicates that astrocytes may act as neural stem cells and contribute to adult neurogenesis. In previous reports, freshly isolated O-2A progenitors were shown to revert to neural stem-like cells (NSLCs) when cultured with a serum-containing glial medium or bone morphogenic proteins for 3 days and with basic fibroblast growth factor consecutively. NSLCs possess self-renewal and multipotential capacities that can give rise to neurons and glial cells, which suggests that they have stem cell-like properties. However, the underlying molecular mechanisms and cell fate commitment when exposed to a neural conditioned medium remain obscure. In this study, we demonstrated that NSLCs grown in the serum-containing neurobasal medium can differentiate into induced neural-like cells (iNLCs). It was noteworthy that astroglia mixed in these cells, particularly in iNLCs, were gradually replaced by neural phenotypes during this glia-neuron conversion. Remarkably, these glial cells can maintain high levels of proliferation and self-renewal ability by activating the NF-κB and MAPK signals. Finally, we found that Notch, STAT3, autophagy, bHLH, and Wnt signals appear to be critical modulators of these intricate events. Altogether, these data demonstrate that O-2A lineage astroglia can function as neural stem cells and display neurogenic plasticity. Dissecting the regulatory pathways involved in these processes is essential to the understanding of glial cell fate and its precise functions. This finding may foster a better understanding of astrocytic heterogeneity and lead to innovative ways to readily apply stem-like astroglia cells as candidate cell sources for neural repair.

Lineage Tracking and Differentiation of Neuro 2A cells (N2a) upon exposure to Dopamine, Monosodium Glutamate and Corticosterone

Cell to cell communication is critical for survival of an organism and it is achieved through signal transduction pathways. For the transmission of signal, molecules such as hormones can bind to a receptor on or inside the cell membrane. Dopamine (DA) a monoamine catecholamine neurotransmitter and hormone binds to dopamine receptor, inturn, affect movement, emotions and the reward system in the brain. The present study tested the hypothesis that Dopamine differentiates the N2a cells into neuronal lineage, and corticosterone (CORT) and monosodium glutamate (MSG) alter the differentiation in either way. Mouse neural crest‐derived cell line (Neuro2A cells, N2a cells) were treated with 10µM DA, MSG and CORT. Cells were seeded for different time points to track the lineage pattern of differentiation. Treatment was done for 24 hrs, 48 hrs, 72hrs and 96 hrs with respective control groups. Phase contrast microscopic images revealed that Dopamine treated cells showed neurite extensions and differentiation as time passed whereas CORT and MSG treatments suppressed the differentiation; the cells were round and showed signs of stress, cell death and autophagy. Immunocytochemical analysis with D1 receptor antibody indicated enhanced expression in the DA groups and diminished D1 receptor expression in CORT and MSG groups. Furthermore, quantitative analysis revealed that D1 receptor expression was significantly enhanced in DA group compared to the control group (medium containing ascorbic acid and phosphate buffered saline) and untreated control group (medium only). Interestingly D1 receptor expression in the DA group was significantly upregulated compared to the CORT group but not significantly different in the MSG group. Furthermore, inorder to assess apoptosis AnnexinV/Propidium Iodide (PI) staining was done using Fluorescence Assorted single cell sorter (FACS) Analysis. Immunolabeling with Caspase‐3 marker gene was done to detect apoptosis. N2a cells were treated with DA, CORT and MSG at 10 µM concentration for 24 hrs. Propidium iodide labelled cells that were already dead or in the late stage of apoptosis whereas Annexin V bound to the cells early in apoptosis and continued to be bound through cell death. Counting of the cells showed that MSG induced 1.8 % apoptosis, CORT induced 1.2 % and DA induced 1.1%, as against control group cells of 0.7 %. The total cell death including apoptosis and necrosis was highest in the MSG group (3.4%) compared to the control (1.7 %), DA (2.1%) and CORT (1.9%) treated groups. This data suggest differential effects elicited by DA (happy hormone) versus stress hormone. Our results also raise the question whether DA induces catecholaminergic pathway of differentiation, CORT stimulates glial type differentiation and MSG stimulates glutamate or GABA differentiation ‐ questions to be answered in future studies.

Streptococcus agalactiae Infects Glial Cells and Invades the Central Nervous System via the Olfactory and Trigeminal Nerves.

Streptococcus agalactiae causes neonatal meningitis and can also infect the adult central nervous system (CNS). S. agalactiae can cross the blood-brain barrier but may also reach the CNS via other paths. Several species of bacteria can directly invade the CNS via the olfactory and trigeminal nerves, which extend between the nasal cavity and brain and injury to the nasal epithelium can increase the risk/severity of infection. Preterm birth is associated with increased risk of S. agalactiae infection and with nasogastric tube feeding. The tubes, also used in adults, can cause nasal injuries and may be contaminated with bacteria, including S. agalactiae. We here investigated whether S. agalactiae could invade the CNS after intranasal inoculation in mice. S. agalactiae rapidly infected the olfactory nerve and brain. Methimazole-mediated model of nasal epithelial injury led to increased bacterial load in these tissues, as well as trigeminal nerve infection. S. agalactiae infected and survived intracellularly in cultured olfactory/trigeminal nerve- and brain-derived glia, resulting in cytokine production, with some differences between glial types. Furthermore, a non-capsulated S. agalactiae was used to understand the role of capsule on glial cells interaction. Interestingly, we found that the S. agalactiae capsule significantly altered cytokine and chemokine responses and affected intracellular survival in trigeminal glia. In summary, this study shows that S. agalactiae can infect the CNS via the nose-to-brain path with increased load after epithelial injury, and that the bacteria can survive in glia.

Diversity of satellite glia in sympathetic and sensory ganglia.

Satellite glia are the major glial type found in sympathetic and sensory ganglia in the peripheral nervous system, and specifically, contact neuronal cell bodies. Sympathetic and sensory neurons differ in morphological, molecular, and electrophysiological properties. However, the molecular diversity of the associated satellite glial cells remains unclear. Here, using single-cell RNA sequencing analysis, we identify five different populations of satellite glia from sympathetic and sensory ganglia. We define three shared populations of satellite glia enriched in immune-response genes, immediate-early genes, and ion channels/ECM-interactors, respectively. Sensory- and sympathetic-specific satellite glia are differentially enriched for modulators of lipid synthesis and metabolism. Sensory glia are also specifically enriched for genes involved in glutamate turnover. Furthermore, satellite glia and Schwann cells can be distinguished by unique transcriptional signatures. This study reveals the remarkable heterogeneity of satellite glia in the peripheral nervous system.

Müller Cell Molecular Heterogeneity: Facts and Predictions.

The retina was historically considered as an “approachable part of the brain”; advantageous, for its simplicity, to use as a model organ for deciphering cellular and molecular mechanisms underlying physiology and pathology of the nervous system. However, the most relevant discoveries arise precisely from unveiling the complexity of the retina. A complexity that partially relies on the layered organization of an extended variety of specialized neuronal and glial cellular types and subtypes. Based on functional, morphological or transcriptome data, over 40 subtypes of retinal ganglion cells or 60 subtypes of retinal amacrine cells have been described. A high degree of specialization, that may lead to segregation into functionally diverse subtypes, is also conceivable for Müller cells, a pleiotropic glial component of all vertebrate retinas. The essential role of Müller glia in retinal homeostasis maintenance involves participation in structural, metabolic and intercellular communication processes. Additionally, they are the only retinal cells that possess regenerative potential in response to injury or disease, and thus may be considered as therapeutic tools. In the assumption that functional heterogeneity might be driven by molecular heterogeneity this review aims to compile emerging evidence that could broaden our understanding of Müller cell biology and retinal physiology.Summary statementMüller glial cells exert multiple essential functions in retinal physiology and retinopathies reflecting perhaps the existence of distinct Müller cellular subpopulations. Harnessing Müller cell heterogeneity may serve to enhance new therapeutic approaches for retinal disease.

Excitatory neurotransmission activates compartmentalized calcium transients in Müller glia without affecting lateral process motility.

Neural activity has been implicated in the motility and outgrowth of glial cell processes throughout the central nervous system. Here, we explore this phenomenon in Müller glia, which are specialized radial astroglia that are the predominant glial type of the vertebrate retina. Müller glia extend fine filopodia-like processes into retinal synaptic layers, in similar fashion to brain astrocytes and radial glia that exhibit perisynaptic processes. Using two-photon volumetric imaging, we found that during the second postnatal week, Müller glial processes were highly dynamic, with rapid extensions and retractions that were mediated by cytoskeletal rearrangements. During this same stage of development, retinal waves led to increases in cytosolic calcium within Müller glial lateral processes and stalks. These regions comprised distinct calcium compartments, distinguished by variable participation in waves, timing, and sensitivity to an M1 muscarinic acetylcholine receptor antagonist. However, we found that motility of lateral processes was unaffected by the presence of pharmacological agents that enhanced or blocked wave-associated calcium transients. Finally, we found that mice lacking normal cholinergic waves in the first postnatal week also exhibited normal Müller glial process morphology. Hence, outgrowth of Müller glial lateral processes into synaptic layers is determined by factors that are independent of neuronal activity.

ACSA-2 and GLAST classify subpopulations of multipotent and glial-restricted cerebellar precursors.

The formation of the cerebellum is highly coordinated to obtain its characteristic morphology and all cerebellar cell types. During mouse postnatal development, cerebellar progenitors with astroglial‐like characteristics generate mainly astrocytes and oligodendrocytes. However, a subset of astroglial‐like progenitors found in the prospective white matter (PWM) produces astroglia and interneurons. Characterizing these cerebellar astroglia‐like progenitors and distinguishing their developmental fates is still elusive. Here, we reveal that astrocyte cell surface antigen‐2 (ACSA‐2), lately identified as ATPase, Na+/K+ transporting, beta 2 polypeptide, is expressed by glial precursors throughout postnatal cerebellar development. In contrast to common astrocyte markers, ACSA‐2 appears on PWM cells but is absent on Bergmann glia (BG) precursors. In the adult cerebellum, ACSA‐2 is broadly expressed extending to velate astrocytes in the granular layer, white matter astrocytes, and to a lesser extent to BG. Cell transplantation and transcriptomic analysis revealed that marker staining discriminates two postnatal progenitor pools. One subset is defined by the co‐expression of ACSA‐2 and GLAST and the expression of markers typical of parenchymal astrocytes. These are PWM precursors that are exclusively gliogenic. They produce predominantly white matter and granular layer astrocytes. Another subset is constituted by GLAST positive/ACSA‐2 negative precursors that express neurogenic and BG‐like progenitor genes. This population displays multipotency and gives rise to interneurons besides all glial types, including BG. In conclusion, this work reports about ACSA‐2, a marker that in combination with GLAST enables for the discrimination and isolation of multipotent and glia‐committed progenitors, which generate different types of cerebellar astrocytes.

Antimicrobial responses of peripheral and central nervous system glia against Staphylococcus aureus

Staphylococcus aureus infections of the central nervous system are serious and can be fatal. S. aureus is commonly present in the nasal cavity, and after injury to the nasal epithelium it can rapidly invade the brain via the olfactory nerve. The trigeminal nerve constitutes another potential route of brain infection. The glia of these nerves, olfactory ensheathing cells (OECs) and trigeminal nerve Schwann cells (TgSCs), as well as astrocytes populating the glia limitans layer, can phagocytose bacteria. Whilst some glial responses to S. aureus have been studied, the specific responses of different glial types are unknown. Here, we compared how primary mouse OECs, TgSCs, astrocytes and microglia responded to S. aureus. All glial types internalized the bacteria within phagolysosomes, and S. aureus-conjugated BioParticles could be tracked with subtle but significant differences in time-course of phagocytosis between glial types. Live bacteria could be isolated from all glia after 24 h in culture, and microglia, OECs and TgSCs exhibited better protection against intracellular S. aureus survival than astrocytes. All glial types responded to the bacteria by cytokine secretion. Overall, OECs secreted the lowest level of cytokines, suggesting that these cells, despite showing strong capacity for phagocytosis, have immunomodulatory functions that can be relevant for neural repair.

Spleen glia are a transcriptionally unique glial subtype interposed between immune cells and sympathetic axons.

Glia are known to play important roles in the brain, the gut, and around the sciatic nerve. While the gut has its own specialized nervous system, other viscera are innervated solely by autonomic nerves. The functions of glia that accompany autonomic innervation are not well known, even though they are one of the most abundant cell types in the peripheral nervous system. Here, we focused on non-myelinating Schwann cells in the spleen, spleen glia. The spleen is a major immune organ innervated by the sympathetic nervous system, which modulates immune function. This interaction is known as neuroimmune communication. We establish that spleen glia can be visualized using both immunohistochemistry for S100B and GFAP and with a reporter mouse. Spleen glia ensheath sympathetic axons and are localized to the lymphocyte-rich white pulp areas of the spleen. We sequenced the spleen glia transcriptome and identified genes that are likely involved in axonal ensheathment and communication with both nerves and immune cells. Spleen glia express receptors for neurotransmitters made by sympathetic axons (adrenergic, purinergic, and Neuropeptide Y), and also cytokines, chemokines, and their receptors that may communicate with immune cells in the spleen. We also established similarities and differences between spleen glia and other glial types. While all glia share many genes in common, spleen glia differentially express genes associated with immune responses, including genes involved in cytokine-cytokine receptor interactions, phagocytosis, and the complement cascade. Thus, spleen glia are a unique glial type, physically and transcriptionally poised to participate in neuroimmune communication in the spleen.

Key differences between olfactory ensheathing cells and Schwann cells regarding phagocytosis of necrotic cells: implications for transplantation therapies

Transplantation of peripheral nervous system glia is being explored for treating neural injuries, in particular central nervous system injuries. These glia, olfactory ensheathing cells (OECs) and Schwann cells (SCs), are thought to aid regeneration by clearing necrotic cells, (necrotic bodies, NBs), as well as myelin debris. The mechanism by which the glia phagocytose and traffic NBs are not understood. Here, we show that OECs and SCs recognize phosphatidylserine on NBs, followed by engulfment and trafficking to endosomes and lysosomes. We also showed that both glia can phagocytose and process myelin debris. We compared the time-course of glial phagocytosis (of both NBs and myelin) to that of macrophages. Internalization and trafficking were considerably slower in glia than in macrophages, and OECs were more efficient phagocytes than SCs. The two glial types also differed regarding their cytokine responses after NB challenge. SCs produced low amounts of the pro-inflammatory cytokine TNF-α while OECs did not produce detectable TNF-α. Thus, OECs have a higher capacity than SCs for phagocytosis and trafficking, whilst producing lower amounts of pro-inflammatory cytokines. These findings suggest that OEC transplantation into the injured nervous system may lead to better outcomes than SC transplantation.

Loss of PRMT1 in the central nervous system (CNS) induces reactive astrocytes and microglia during postnatal brain development

PRMT1, a major arginine methyltransferase, plays critical roles in transcription, DNA damage response, and cell proliferation. Although we have previously discovered the crucial roles of PRMT1 for oligodendrocyte lineage progression in the central nervous system of neural stem cell-specific PRMT1 conditional knockout (PRMT1-CKO) mice, the context of other glial cell states that may cause the hypomyelination phenotype in PRMT1-CKO mice has not been explored so far. Here, we performed RNA-seq of the neonatal cortices of PRMT1-CKO mice to reveal overall gene expression changes and show the up-regulation of inflammatory signaling which is generally mediated by astrocytes and microglia in advance of the myelination defects. In particular, qRT-PCR analyses revealed Interleukin-6 (Il-6), a major central nervous system cytokine, was dramatically increased in the PRMT1-CKO brains. The gene expression changes led to augmentation of glial fibrillary acidic protein and Vimentin protein levels in PRMT1-CKO mice, showing severe reactive astrogliosis after birth. We further show that IBA1-positive and CD68-positive activated microglia were increased in PRMT1-CKO mice, in spite of intact Prmt1 gene expression in purified microglia from the mutant mice. Our results indicate that PRMT1 loss in the neural stem cell lineage causes disruptive changes in all glial types perturbing postnatal brain development and myelination.

Clinical and pathologic features of cognitive-predominant corticobasal degeneration.

ObjectiveTo describe clinical and pathologic characteristics of corticobasal degeneration (CBD) with cognitive predominant problems during the disease course.MethodsIn a series of autopsy-confirmed cases of CBD, we identified patients with cognitive rather than motor predominant features (CBD-Cog), including 5 patients thought to have Alzheimer disease (AD) and 10 patients thought to have behavioral variant frontotemporal dementia (FTD). We compared clinical and pathologic features of CBD-Cog with those from a series of 31 patients with corticobasal syndrome (CBD-CBS). For pathologic comparisons between CBD-Cog and CBD-CBS, we used semiquantitative scoring of neuronal and glial lesion types in multiple brain regions and quantitative assessments of tau burden from image analysis.ResultsFive of 15 patients with CBD-Cog never had significant motor problems during their disease course. The most common cognitive abnormalities in CBD-Cog were executive and visuospatial dysfunction. The frequency of language problems did not differ between CBD-Cog and CBD-CBS. Argyrophilic grain disease, which is a medial temporal tauopathy associated with mild cognitive impairment, was more frequent in CBD-Cog. Apathy was also more frequent in CBD-Cog. Tau pathology in CBD-Cog was greater in the temporal and less in perirolandic cortices than in CBD-CBS.ConclusionA subset of patients with CBD has a cognitive predominant syndrome than can be mistaken for AD or FTD. Our findings suggest that distribution of tau cortical pathology (greater in temporal and less in perirolandic cortices) may be the basis of this uncommon clinical variant of CBD.