Biology subjects

Cohen-Salmon, M.

Publications and source records attributed to Cohen-Salmon, M..

15 recordsLinked to original sources

bioRxiv2026

Neocortical astrocyte diversity stems from distinct developmental origins

Key regulators of neural network activity in multiple advanced cognitive processes and essential components of the blood-brain barrier, astrocytes constitute a highly heterogeneous population at the morphological, molecular, and functional levels. However, how this diversity arises during mammalian brain development remains poorly investigated. Here, using a combination of multicolour genetic fate mapping, single-cell transcriptomic analyses, multichannel large-volume imaging and detailed 3D cell morphology reconstructions, we uncover a discrete subpopulation of neocortical astrocytes generated from an early restricted embryonic domain located outside of the dorsal pallium. Besides their separate lineage from pyramidal neurons, these astrocytes exhibit a developmental trajectory that differs from astrocytes produced by dorsal cortical progenitors, including different migratory pathways, spatial distributions and morphology. Overall, our results reveal the diversity of embryonic sources responsible for neocortical astrocyte genesis and provide key insights into the unsuspected complex developmental processes that underlie cortical astrocyte heterogeneity.

neuroscience↗

bioRxiv2026

Sex influences gliovascular unit assembly and function in the developing mouse brain

The gliovascular unit (GVU), a specialized interface between the brain and the vascular system, assembles and matures after birth and establishes essential homeostatic functions, including blood-brain barrier integrity, metabolic exchanges, fluid drainage, neurovascular coupling, and immune surveillance. Here, we systematically compared the postnatal maturation of the cortical GVU in male vs. female mice. On P15, males exhibited a transiently greater vessel density and a higher level of aquaporin 4 expression in perivascular astrocyte processes. Females exhibited a higher density of perivascular macrophages expressing the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1), along with earlier development of arterial vascular smooth muscle cells and greater cerebral blood flow. Transcriptomic profiling during the P5-P120 period revealed sex-specific developmental trajectories within the GVU, with the most prominent differences on P5. Taken as a whole, our results highlight pronounced sex-dependent differences in GVU assembly, GVU maturation, and the development of molecular programs that might influence brain physiology and vulnerability to neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Organelle distribution and protein translation defects in radial glia cells with mutations in Eml1

Cerebral cortical development is a finely regulated process, depending on key neuronal progenitors, giving rise to post-mitotic neurons that migrate to superficial regions in the developing brain. Disruptions can give rise to severe cortical malformations that are associated with intellectual disability and intractable epilepsy. Mutations in EML1/Eml1, coding for a microtubule (MT)-associated protein, lead to subcortical heterotopia (SH) in both humans and mice. In developing mutant mouse brains, ectopic apical radial glia (aRG) progenitors were found outside the normal proliferative ventricular zone (VZ). The normal role of Eml1 in these cells remains to be precisely determined. Using proteomics and imaging approaches, we compared brain tissue from control and mutant mice and identified microtubule and organelle dysregulation. Eml1 influences the trafficking of organelles to different compartments of aRG, where they may be involved in local functions. Thus, we find that mitochondrial and polysome distribution are altered in mutant conditions. Indeed, Eml1 interacts with translational machinery, and an overall downregulation of translation is observed when analysing the translatome of Eml1 mutant aRG. Paradoxically, an upregulation of translation-related mRNAs is also observed. These new data uncover an unprecedented function of Eml1, as well as associating novel subcellular patho-mechanisms with severe heterotopia formation.

neuroscience↗

bioRxiv2025

Local translation controls early reactive changes in perisynaptic astrocyte processes at pre-symptomatic stages of Alzheimer s disease

Early synaptic dysfunction is a hallmark of Alzheimers disease (AD), yet the astrocytic mechanisms underlying these alterations remain poorly defined. Here, we identify astrocyte perisynaptic processes (PAPs) as subcellular hotspots of early translational dysregulation in AD. Soluble A{beta}-2 rapidly enhanced global and local protein synthesis in primary astrocytes. In 5.5-month-old APP/PS1-dE9 (APP) mice, translating ribosome affinity purification (TRAP) revealed widespread remodeling of the PAP translatome, while whole-astrocyte translation remained largely unchanged. Dysregulated mRNAs were linked to neuroinflammation, synaptic remodeling, and endoplasmic reticulum stress, and alterations emerged prior to amyloid plaque deposition. Among them, Serpina3n exhibited increased mRNA abundance in PAPs, uncovering spatially restricted translational control. Mechanistically, early Serpina3n upregulation was partially driven by JAK-STAT3 signaling, with preferential effects in astrocyte processes. These findings reveal that local translation in astrocyte PAPs is an early and compartment-specific mechanism that may contribute to synaptic dysfunction and disease initiation in AD.

neuroscience↗

bioRxiv2025

VeCell: A Fiji Plugin to unveil the spatio-temporal dynamics of macroglial cell development and proximity to blood vessels

Brain cortical development results from the proliferation, differentiation, migration and maturation of many cell types. While neuronal development is well characterized, the mechanisms regulating macroglial cells (oligodendrocytes and astrocytes) development remain largely unknown. Recent works suggest that the vascular system plays a key, yet under-evaluated role in this process. In this study, we investigated the spatial organization of macroglial cells within the parenchyma and relative to blood vessels. Using immunolabeling for Sry-box transcription factor (Sox) 9 (macroglial progenitors and astrocytes) and Sox10 (oligodendrocyte lineage), we determined macroglia density, distribution and proximity to blood vessels from postnatal day (P) 1 to P60 in the somatosensory cortex. We showed that Sox9+ cells were evenly distributed across cortical layers with regular intercellular spacing. In contrast, Sox10+ cells concentrated in deeper cortical layers, and exhibited a random distribution. Vascular density and branching increased markedly between P5 and P15 and macroglial cells were closer to blood vessels from P15 onward. We investigated possible alteration of astrocyte distribution in the cortex of MLC1-deficient mice, a model of Megalencephalic leukoencephalopathy with subcortical cysts, in which astrocyte perivascular coverage is altered. No difference with the control condition were found both in young and adult mice, either in the density, distribution or distance to blood vessels. Altogether, we revealed distinct distribution and postnatal development patterns for astrocytes and oligodendrocytes in the brain and in relation to the vasculature. Table of Contents Entry O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/632893v3_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@10ab9f2org.highwire.dtl.DTLVardef@135c06dorg.highwire.dtl.DTLVardef@1ec4f65org.highwire.dtl.DTLVardef@1509f08_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIFrom P5, Sox9 cells are evenly distributed, unlike Sox10 cells C_LIO_LIFrom P15, Sox9 cells are located closer to blood vessels than Sox10 cells C_LIO_LIDistribution of astrocytes is not altered in Mlc1 KO cortex C_LI

neuroscience↗

bioRxiv2024

Vascular dysfunction is at the onset of oxaliplatin-induced peripheral neuropathy symptoms in mice

Oxaliplatin-induced peripheral neuropathy (OIPN) is an adverse side effect of this chemotherapy used for gastrointestinal cancers. The continuous pain experienced by OIPN patients often result in the reduction or discontinuation of chemotherapy, thereby affecting patient survival. Several pathogenic mechanisms involving sensory neurons were shown to participate in the occurrence of OIPN symptoms. However, the dysfunction of the blood-nerve barrier as a source of nerve alteration had not been thoroughly explored. To characterise the vascular contribution to OIPN symptoms, we undertook two comparative transcriptomic analyses from mouse purified brain and sciatic nerve blood vessels (BVs), and nerve BVs after oxaliplatin or control administration. These analyses reveal distinct molecular landscapes between brain and nerve BVs and the upregulation of transcripts involved in vascular contraction after oxaliplatin treatment. Anatomical examination of the nerve yet shows the preservation of BV architecture in acute OIPN mouse model, although treated mice exhibit both neuropathic symptoms and enhanced vasoconstriction reflected by hypoxia. Moreover, vasodilators significantly reduce oxaliplatin-induced neuropathic symptoms and endoneurial hypoxia, establishing the key involvement of nerve blood flow in OIPN.

neuroscience↗

bioRxiv2023

Dynamic local mRNA distribution and translation influence the postnatal molecular maturation of perivascular astrocytic processes

Astrocytes (the main glial cells in the brain) are highly ramified and send out perivascular processes (PvAPs) that entirely sheathe the brains blood vessels. PvAPs are equipped with an enriched molecular repertoire that sustains astrocytic regulatory functions at the vascular interface. In the mouse, PvAP development starts after birth and is essentially complete by postnatal day (P) 15. Progressive molecular maturation also occurs over this period, with the acquisition of proteins enriched in PvAPs. The mechanisms controlling the development and molecular maturation of PvAPs have not been extensively characterized. We reported previously that mRNAs are distributed unequally in mature PvAPs and are locally translated. Since dynamic mRNA distribution and local translation influence the cells polarity, we hypothesized that they might sustain the postnatal maturation of PvAPs. Here, we used a combination of molecular biology and imaging approaches to demonstrate that the development of PvAPs is accompanied by the transport of mRNA and polysomal mRNA into PvAPs, the development of a rough endoplasmic reticulum (RER) network and Golgi cisternae, and local translation. By focusing on genes and proteins that are selectively or specifically expressed in astrocytes, we characterized the developmental profile of mRNAs, polysomal mRNAs and proteins in PvAPs from P5 to P60. Furthermore, we found that distribution of mRNAs in PvAPs is perturbed in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts. Lastly, we found that some polysomal mRNAs polarized progressively towards the PvAPs. Our results indicate that dynamic mRNA distribution and local translation influence the postnatal maturation of PvAPs. Summary statementLocal translation operates during the postnatal development of perivascular astrocyte processes and might contribute to their molecular maturation.

neuroscience↗

bioRxiv2023

Evaluation of gliovascular functions of Aqp4 readthrough isoforms

Aquaporin-4 (AQP4) is a water channel protein that links astrocytic endfeet to the blood-brain barrier (BBB) and regulates water and potassium homeostasis in the brain, as well as the glymphatic clearance of waste products that would otherwise potentiate neurological diseases. Recently, translational readthrough was shown to generate a C-terminally extended variant of AQP4, known as AQP4x, that preferentially localizes around the BBB through interaction with the scaffolding protein -syntrophin, and loss of AQP4x disrupts waste clearance from the brain. To investigate the function of AQP4x, we generated a novel mouse AQP4 line (AllX) to increase relative levels of the readthrough variant above the [~]15% of AQP4 in the brain of wildtype (WT) mice. We validated the line and assessed characteristics that are affected by the presence of AQP4x, including AQP4 and -syntrophin localization, integrity of the BBB, and neurovascular coupling. We compared AllXHom and AllXHet mice to wildtype, and to previously characterized AQP4 NoXHet and NoXHom mice, which cannot produce AQP4x. Increased dose of AQP4x enhanced perivascular localization of - syntrophin and AQP4, while total protein expression of the two were unchanged. However, at 100% readthrough, AQP4x localization and formation of higher-order complexes was disrupted. Electron microscopy showed that overall blood vessel morphology was unchanged except for increased endothelial cell vesicles in NoXHom mice, which may correspond to a leakier BBB or altered efflux that was identified in NoX mice using MRI. These data demonstrate that AQP4x plays a small but measurable role in maintaining BBB integrity as well as recruiting structural and functional support proteins to the blood vessel. This also establishes a new set of genetic tools for quantitatively modulating AQP4x levels. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/549379v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@18f8f32org.highwire.dtl.DTLVardef@25afeorg.highwire.dtl.DTLVardef@a3e0e1org.highwire.dtl.DTLVardef@100f2e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Translational regulation by RACK1 in astrocytes represses KIR4.1 expression and regulates neuronal activity

The regulation of translation in astrocytes, the main glial cells in the brain, remains poorly characterized. We developed a high-throughput proteomic screen for polysome-associated proteins in astrocytes and focused on the ribosomal protein receptor of activated protein C kinase 1 (RACK1), a critical factor in translational regulation. In astrocyte somata and perisynaptic astrocytic processes (PAPs), RACK1 preferentially bound to a number of mRNAs, including Kcnj10, encoding the inward rectifying potassium (K+) channel KIR4.1, a critical astrocytic regulator of neurotransmission. By developing an astrocyte-specific, conditional RACK1 knock-out mouse model, we showed that RACK1 repressed the production of KIR4.1 in hippocampal astrocytes and PAPs. Reporter-based assays revealed that RACK1 controlled Kcnj10 translation through the transcripts 5 untranslated region. Upregulation of KIR4.1 in the absence of RACK1 modified the astrocyte territory volume and neuronal activity attenuatin burst frequency and duration in the hippocampus. Hence, astrocytic RACK1 represses KIR4.1 translation and influences neuronal activity.

neuroscience↗

bioRxiv2022

Physiopathological changes of ferritin mRNA density and distribution in hippocampal astrocytes in the mouse brain

Astrocytes are thought to play a crucial role in brain iron homeostasis. How they accomplish this regulation in vivo remains unclear. In a recent transcriptomic analysis, we showed that polysomal Ftl1 and Fth1 mRNAs, encoding the ferritin light (Ftl) and heavy (Fth) chains that assemble into ferritin, a critical complex for iron storage and reduction, are enriched in perisynaptic astrocytic processes as compared to astrocytic soma. These data suggested that ferritin translation plays a specific role at the perisynaptic astrocytic interface and is tighly regulated by local translation. Here, we used our recently described AstroDot 3D in situ methodology to study the density and localization of ferritin mRNAs in astrocytes in the hippocampus in three different contexts in which local or systemic iron overload has been documented: ageing, the hepcidin knock-out mouse model of hemochromatosis and the APP/PS1dE9 mouse model of Alzheimers disease (AD). Our results showed that in wild type mice, Fth1 mRNA density was higher than Ftl1 and that both mRNAs were mostly distributed in astrocyte fine processes. Ageing and absence of hepcidin caused an increased Fth1/Ftl1 ratio in astrocytes and in the case of ageing, led to a redistribution of Fth1 mRNAs in astrocytic fine processes. In contrast, in AD mice, we observed a lower Fth1/Ftl1 ratio and Fth1 mRNAs became more somatic. Hence, we propose that regulation of ferritin mRNA density and distribution in astrocytes regulates iron homeostasis in physiology and pathophysiology.

neuroscience↗

bioRxiv2021

Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC); this rare type of leukodystrophy is characterized by early-onset macrocephaly and progressive white matter vacuolation that lead to ataxia, spasticity, and cognitive decline. During postnatal development (from P5 to P15 in the mouse), MLC1 forms a membrane complex with GlialCAM (another astrocytic transmembrane protein) at the junctions between perivascular astrocytic processes (PvAPs, which along with blood vessels form the gliovascular unit (GVU)). We analyzed the GVU in the Mlc1 knock-out mouse model of MLC. The absence of MLC1 led to an accumulation of fluid in the brain but did not modify the endothelial organization or the integrity of the blood-brain barrier. From P10 onward, the postnatal acquisition of vascular smooth muscle cell contractility was altered, resulting in a marked reduction in arterial perfusion and neurovascular coupling. These anomalies were correlated with alterations in astrocyte morphology, astrocyte polarity and the structural organization of the PvAPs perivascular coverage, and poor intraparenchymal circulation of the cerebrospinal fluid (CSF). Hence, MLC1 is required for the postnatal development and organization of PvAPs and controls vessel contractility and intraparenchymal interstitial fluid clearance. Our data suggest that (i) MLC is a developmental disorder of the GVU, and (ii) PvAP and VSMC maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.

neuroscience↗

bioRxiv2021

In mice and humans, the brain's blood vessels mature postnatally to acquire barrier and contractile properties

The brain dense vascular network is essential for distributing oxygen and nutrients to neural cells. The network develops during embryogenesis and leads to the formation of the endothelial blood-brain barrier (BBB). This barrier is surrounded by mural cells (pericytes and vascular smooth muscle cells (VSMCs)) and fibroblasts. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific or -preferentially expressed transcripts. We found that endothelial cells (ECs), VSMCs and fibroblasts follow specific molecular maturation programs over this time period. In particular, ECs acquire P-glycoprotein (P-gP)-mediated efflux capacities. The arterial VSMC network expands, acquires contractile proteins (such as smooth muscle actin (SMA) and myosin heavy chain 11 (Myh11)) and becomes contractile. We also analyzed samples of human brain cortex from the early prenatal stage through to adulthood: the expression of endothelial P-gP increased at birth and Myh11 in VSMCs acts as a developmental switch (as in the mouse) at birth and up to the age of 2 of 5 years. Thus, in both mice and humans, the early postnatal phase is a critical period during which the essential properties of cerebral blood vessels (i.e. the endothelial efflux of xenobiotics and other molecules, and the VSMC contractility required for vessel tone and brain perfusion) are acquired and mature.

neuroscience↗

bioRxiv2020

Local translation in perisynaptic astrocytic processes is specific and regulated by fear conditioning

Local translation is a conserved molecular mechanism conferring cells the ability to quickly respond to local stimuli. It not only permits cells with complex morphology to bypass somatic protein synthesis and transport, but also contributes locally to the establishment of molecular and functional polarity. In the brain, local translation has been extensively studied in neurons and has only been recently reported in astrocytes, whose fine processes contact both blood vessels and synapses. Yet the specificity and regulation of astrocyte local translation remain unknown. Here, we studied hippocampal perisynaptic astrocytic processes (PAPs) and show that they contain all the machinery for translation. Using our recently refined polysome immunoprecipitation technique, we then characterized the pool of polysomal mRNAs in PAPs, referred to as the PAPome, and compared it to the one found in the whole astrocyte. We found that the PAPome encoded an unexpected molecular repertoire, mostly composed of cytoplasmic proteins and of proteins involved in iron homeostasis, translation, cell cycle and cytoskeleton. Among them, ezrin (Ezr), ferritin heavy chain 1 (Fth1) and 60S acidic ribosomal protein1 (Rplp1) were enriched in PAPs compared to perivascular astrocytic processes, indicating that local translation differs at these two interfaces. Remarkably, PAPs were also enriched in transcripts coding for proteins involved in learning and memory, such as ferritin (Ftl1 and Fth1), G1/S-specific cyclin-D2 (Ccnd2), E3 ubiquitin-protein ligase (Mdm2), Receptor of activated protein C kinase 1 (Gnb2l1) and Elongation factor 1-alpha 1 (Eef1a1). To address their regulation in a physiological context, we assessed their local translation after fear conditioning. We found alterations in their density and/or distribution in astrocytes as well as a drop in their translation specifically in PAPs. In all, our results reveal an unexpected molecular repertoire of hippocampal PAPs, which is regulated by local translation during learning and memory processes.

neuroscience↗

bioRxiv2020

Role of astrogial Connexin 43 in pneumococcal meningitis and pneumolysin cytotoxicity

Introductory paragraphStreptococcus pneumoniae or pneumococcus (PN) is a major causative agent of bacterial meningitis with high mortality in young infants and elderly people. The mechanism underlying PN crossing of the blood brain barrier (BBB) remains poorly understood. Here, we show that the gap junctional component connexin 43 expressed in astrocytes (aCx43) plays a major role in PN meningitis. Following intravenous PN challenge, mice deficient for aCx43 developed milder symptoms and showed severely reduced bacterial counts in the brain. We show a role for aCx43 in the PN-induced fragmentation of astrocytic GFAP filaments associated with bacterial translocation across endothelial vessels and replication in the brain cortex. aCx43 triggers the PN- and Ply-dependent GFAP fragmentation and nuclear shrinkage in in vitro cultured astrocytes. We showed that purified pneumolysin (Ply) co-opted Cx43 to promote the permeabilization and cytosolic calcium (Ca2+) increase of host cells, a process sensitive to extracellular ATP depletion. These results point to aCx43 as a major player during bacterial meningitis and extend cytolytic mechanisms implicating other host cell plasma membrane channels proposed for small pore-forming toxins, to Ply, a cholesterol-dependent cytolysin, at concentrations relevant to bacterial infection.

microbiology↗

bioRxiv2019

AstroDot: a new method for studying the spatial distribution of mRNA in astrocytes

Cells with a complex shape often use mRNA distribution and local translation to regulate distal functions. These mechanisms have recently been described in astrocytes, the processes of which contact and functionally modulate neighbouring synapses and blood vessels. In order to study the distribution of mRNA in astrocytes, we developed a three-dimensional histological method that combines mRNA detection via in situ hybridization with immunostaining of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). Three-dimensional confocal images were analyzed using AstroDot, a custom Image J plug-in developed in-house for the identification and quantification of mRNAs in GFAP-immunolabelled astrocyte somata, large processes and fine processes. The custom R package AstroStat was used to analyze the AstroDot results. Taking the characterization of mRNAs encoding the astrocyte-specific GFAP and {delta} isoforms in the hippocampus as a proof of concept, we showed that Gfap and Gfap {delta} mRNAs mainly colocalized with GFAP in astrocyte processes. Gfap mRNA was more abundant than Gfap {delta} mRNA, and was predominantly found in fine processes. Upon glial activation in the APPswe/PS1dE9 mouse model of Alzheimers disease, the same overall patterns were found but we noted strong variations in Gfap and Gfap {delta} mRNA density and distribution as a function of the part of the hippocampus and the astrocytes proximity to beta-amyloid (A{beta}) plaques. In astrocytes not associated with A{beta}, Gfap mRNA levels were only slightly elevated, and Gfap {delta} mRNA was distributed within the fine processes; these effects were more prominent in CA3 than in CA1. In contrast, levels of both mRNAs were markedly elevated in the fine processes of A{beta}-associated astrocytes in both CA1 and CA3. In order to validate our new method, we confirmed that Rpl4 mRNA (a ubiquitously expressed mRNA encoding the large subunit ribosomal protein 4) was present in large and fine processes in both astrocytes and microglia. In summary, we have developed a novel, reliable set of tools for characterizing mRNA densities and distributions in the somata and processes of astrocytes and microglia in physiological or pathological settings. Furthermore, our results suggest that intermediate filaments are crucial for distributing mRNA within astrocytes and for modulating specific Gfap mRNA profiles in Alzheimers disease.

neuroscience↗