23 research outputs found
Oligodendrocyte precursor cells: the multitaskers in the brain
In the central nervous system, oligodendrocyte precursor cells (OPCs) are recognized as the progenitors responsible for the
generation of oligodendrocytes, which play a critical role in myelination. Extensive research has shed light on the mechanisms
underlying OPC proliferation and diferentiation into mature myelin-forming oligodendrocytes. However, recent advances
in the feld have revealed that OPCs have multiple functions beyond their role as progenitors, exerting control over neural
circuits and brain function through distinct pathways. This review aims to provide a comprehensive understanding of OPCs
by frst introducing their well-established features. Subsequently, we delve into the emerging roles of OPCs in modulating brain function in both healthy and diseased states. Unraveling the cellular and molecular mechanisms by which OPCs
infuence brain function holds great promise for identifying novel therapeutic targets for central nervous system diseases
Oligodendroglial GABAergic Signaling: More Than Inhibition!
GABA is the main inhibitory neurotransmitter in the CNS acting at two distinct types of receptor: ligand-gated ionotropic GABAA receptors and G protein-coupled metabotropic GABAB receptors, thus mediating fast and slow inhibition of excitability at central synapses. GABAergic signal transmission has been intensively studied in neurons in contrast to oligodendrocytes and their precursors (OPCs), although the latter express both types of GABA receptor. Recent studies focusing on interneuron myelination and interneuron-OPC synapses have shed light on the importance of GABA signaling in the oligodendrocyte lineage. In this review, we start with a short summary on GABA itself and neuronal GABAergic signaling. Then, we elaborate on the physiological role of GABA receptors within the oligodendrocyte lineage and conclude with a description of these receptors as putative targets in treatments of CNS diseases
Acute brain injuries trigger microglia as an additional source of the proteoglycan NG2
NG2 is a type I transmembrane glycoprotein known as chondroitin sulfate proteoglycan 4 (CSPG4). In the healthy central nervous system, NG2 is exclusively expressed by oligodendrocyte progenitor cells and by vasculature pericytes. A large body of immunohistochemical studies showed that under pathological conditions such as acute brain injuries and experimental autoimmune encephalomyelitis (EAE), a number of activated microglia were NG2 immuno-positive, suggesting NG2 expression in these cells. Alternative explanations for the microglial NG2 labeling consider the biochemical properties of NG2 or the phagocytic activity of activated microglia. Reportedly, the transmembrane NG2 proteoglycan can be cleaved by a variety of proteases to deposit the NG2 ectodomain into the extracellular matrix. The ectodomain, however, could also stick to the microglial surface. Since microglia are phagocytic cells engulfing debris of dying cells, it is difficult to identify a genuine expression of NG2. Recent studies showing (1) pericytes giving rise to microglial after stroke, and (2) immune cells of NG2-EYFP knock-in mice lacking NG2 expression in an EAE model generated doubts for the de novo expression of NG2 in microglia after acute brain injuries. In the current study, we took advantage of three knock-in mouse lines (NG2-CreERT2, CX3CR1-EGFP and NG2-EYFP) to study NG2 expression indicated by transgenic fluorescent proteins in microglia after tMCAO (transient middle cerebral artery occlusion) or cortical stab wound injury (SWI). We provide strong evidence that NG2-expressing cells, including OPCs and pericytes, did not differentiate into microglia after acute brain injuries, whereas activated microglia did express NG2 in a disease-dependent manner. A subset of microglia continuously activated the NG2 gene at least within the first week after tMCAO, whereas within 3Â days after SWI a limited number of microglia at the lesion site transiently expressed NG2. Immunohistochemical studies demonstrated that these microglia with NG2 gene activity also synthesized the NG2 protein, suggesting activated microglia as an additional source of the NG2 proteoglycan after acute brain injuries
A subset of OPCs do not express Olig2 during development which can be increased in the adult by brain injuries and complex motor learning
Oligodendrocyte precursor cells (OPCs) are uniformly distributed in the mammalian
brain; however, their function is rather heterogeneous in respect to their origin, location, receptor/channel expression and age. The basic helix–loop–helix transcription
factor Olig2 is expressed in all OPCs as a pivotal determinant of their differentiation.
Here, we identified a subset (2%–26%) of OPCs lacking Olig2 in various brain regions
including cortex, corpus callosum, CA1 and dentate gyrus. These Olig2 negative
(Olig2neg) OPCs were enriched in the juvenile brain and decreased subsequently with
age, being rarely detectable in the adult brain. However, the loss of this population
was not due to apoptosis or microglia-dependent phagocytosis. Unlike Olig2pos
OPCs, these subset cells were rarely labeled for the mitotic marker Ki67. And, accordingly, BrdU was incorporated only by a three-day long-term labeling but not by a
2-hour short pulse, suggesting these cells do not proliferate any more but were
derived from proliferating OPCs. The Olig2neg OPCs exhibited a less complex morphology than Olig2pos ones. Olig2neg OPCs preferentially remain in a precursor stage
rather than differentiating into highly branched oligodendrocytes. Changing the adjacent brain environment, for example, by acute injuries or by complex motor learning
tasks, stimulated the transition of Olig2pos OPCs to Olig2neg cells in the adult. Taken
together, our results demonstrate that OPCs transiently suppress Olig2 upon changes
of the brain activity
Astrocytic p75NTR expression provoked by ischemic stroke exacerbates the blood-brain barrier disruption
The disruption of the blood–brain barrier (BBB) plays a critical role in the pathology of
ischemic stroke. p75 neurotrophin receptor (p75NTR) contributes to the disruption of
the blood-retinal barrier in retinal ischemia. However, whether p75NTR influences the
BBB permeability after acute cerebral ischemia remains unknown. The present study
investigated the role and underlying mechanism of p75NTR on BBB integrity in an
ischemic stroke mouse model, middle cerebral artery occlusion (MCAO). After 24 h of
MCAO, astrocytes and endothelial cells in the infarct-affected brain area up-regulated
p75NTR. Genetic p75NTR knockdown (p75NTR+/ ) or pharmacological inhibition of
p75NTR using LM11A-31, a selective inhibitor of p75NTR, both attenuated brain damage and BBB leakage in MCAO mice. Astrocyte-specific conditional knockdown of
p75NTR mediated with an adeno-associated virus significantly ameliorated BBB disruption and brain tissue damage, as well as the neurological functions after stroke. Further
molecular biological examinations indicated that astrocytic p75NTR activated NF-ÎşB
and HIF-1α signals, which upregulated the expression of MMP-9 and vascular endothelial growth factor (VEGF), subsequently leading to tight junction degradation after
ischemia. As a result, increased leukocyte infiltration and microglia activation exacerbated brain injury after stroke. Overall, our results provide novel insight into the role of
astrocytic p75NTR in BBB disruption after acute cerebral ischemia. The p75NTR may
therefore be a potential therapeutic target for the treatment of ischemic stroke
Novel algorithms for improved detection and analysis of fluorescent signal fluctuations
Fluorescent dyes and genetically encoded fuorescence indicators (GEFI) are common tools for visualizing concentration
changes of specifc ions and messenger molecules during intra- as well as intercellular communication. Using advanced
imaging technologies, fuorescence indicators are a prerequisite for the analysis of physiological molecular signaling. Automated detection and analysis of fuorescence signals require to overcome several challenges, including correct estimation
of fuorescence fuctuations at basal concentrations of messenger molecules, detection, and extraction of events themselves
as well as proper segmentation of neighboring events. Moreover, event detection algorithms need to be sensitive enough to
accurately capture localized and low amplitude events exhibiting a limited spatial extent. Here, we present two algorithms
(PBasE and CoRoDe) for accurate baseline estimation and automated detection and segmentation of fuorescence fuctuations
Impaired bidirectional communication between interneurons and oligodendrocyte precursor cells affects social cognitive behavior
Cortical neural circuits are complex but very precise networks of balanced excitation and
inhibition. Yet, the molecular and cellular mechanisms that form the balance are just
beginning to emerge. Here, using conditional Îł-aminobutyric acid receptor B1- deficient mice
we identify a Îł-aminobutyric acid/tumor necrosis factor superfamily member 12-mediated
bidirectional communication pathway between parvalbumin-positive fast spiking interneurons and oligodendrocyte precursor cells that determines the density and function of
interneurons in the developing medial prefrontal cortex. Interruption of the GABAergic signaling to oligodendrocyte precursor cells results in reduced myelination and hypoactivity of
interneurons, strong changes of cortical network activities and impaired social cognitive
behavior. In conclusion, glial transmitter receptors are pivotal elements in finetuning distinct
brain functions
Unlocking the Potential: immune functions of oligodendrocyte precursor cells
Oligodendrocyte precursor cells (OPCs) have long been regarded as progenitors
of oligodendrocytes, yet recent advances have illuminated their multifaceted
nature including their emerging immune functions. This review seeks to shed
light on the immune functions exhibited by OPCs, spanning from phagocytosis to
immune modulation and direct engagement with immune cells across various
pathological scenarios. Comprehensive understanding of the immune functions
of OPCs alongside their other roles will pave the way for targeted therapies in
neurological disorders
Genetic background affects human glial fibrillary acidic protein promoter activity.
The human glial fibrillary acidic protein (hGFAP) promoter has been used to generate numerous transgenic mouse lines, which has facilitated the analysis of astrocyte function in health and disease. Here, we evaluated the expression levels of various hGFAP transgenes at different ages in the two most commonly used inbred mouse strains, FVB/N (FVB) and C57BL/6N (B6N). In general, transgenic mice maintained on the B6N background displayed weaker transgene expression compared with transgenic FVB mice. Higher level of transgene expression in B6N mice could be regained by crossbreeding to FVB wild type mice. However, the endogenous murine GFAP expression was equivalent in both strains. In addition, we found that endogenous GFAP expression was increased in transgenic mice in comparison to wild type mice. The activities of the hGFAP transgenes were not age-dependently regulated. Our data highlight the importance of proper expression analysis when non-homologous recombination transgenesis is used