Biology subjects

Escartin, C.

Publications and source records attributed to Escartin, C..

6 recordsLinked to original sources

bioRxiv2026

Acetylcholine drives astrocytic JAK2-STAT3 signaling to modulate male-to-female approach behavior

Astrocytes are essential regulators of neural circuits and behavior, sensing synaptic activity and modulating plasticity through diverse intracellular mechanisms. However, the contribution of astrocyte transcription factor-based cascades, linking external stimuli to long-term transcriptional programs, is currently misunderstood. Here we show that the JAK2-STAT3 signaling plays a critical role in male-to-female social behavior. Hence, in male mice, exposure to estrus females rapidly and selectively induces STAT3 signaling in ventral hippocampal astrocytes. Surprisingly, this induction is not driven through canonical cytokine signaling but by septo-hippocampal cholinergic inputs acting through 7 nicotinic acetylcholine receptors (7nAChR). Astrocytic 7nAChR-JAK2-STAT3 signaling in turn modulates vCA1 pyramidal neuron activity and is required for context-appropriate male approach behavior. These findings reveal a previously unsuspected cellular pathway integrating neuromodulatory inputs and transcription factor-based signaling to shape male behavioral response depending on female receptivity.

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↗

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

The JAK2-STAT3 pathway controls a beneficial proteostasis response of reactive astrocytes in Huntington disease

Huntingtons disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntingtons disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntingtons disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntingtons disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntingtons disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntingtons disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.

neuroscience↗

bioRxiv2019

Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease

In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we recently developed viral vectors targeting astrocytes that either activate or inhibit the JAK2-STAT3 pathway, a central cascade controlling astrocyte reaction.\n\nWe aimed to evaluate whether reactive astrocytes contribute to Tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops Tau hyperphosphorylation and aggregation in addition to amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in the hippocampus of 3xTg-AD mice, did not significantly influence Tau phosphorylation or amyloid processing and deposition, at early, advanced and terminal stage of the disease. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve short-term spatial memory in the Y maze but it reduced anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show these cells may impact behavioral outcomes without influencing Tau or amyloid pathology.

neuroscience↗

bioRxiv2018

Diffusion-weighted magnetic resonance spectroscopy enables cell-specific monitoring of astrocyte reactivity in vivo

The diffusion of brain intracellular metabolites, as measured using diffusion-weighted magnetic resonance spectroscopy in vivo, is thought to specifically depend on the cellular structure constraining them. However, it has never been established that variations of metabolite diffusion, e.g. as observed in some diseases, could indeed be linked to alterations of cellular morphology. Here we demonstrate, in a mouse model of reactive astrocytes, that advanced diffusion-weighted magnetic resonance spectroscopy acquisition and modeling techniques enable non-invasive detection of reactive astrocyte hypertrophy (increased soma radius, increased fiber radius and length), as inferred from variations of myo-inositol diffusion, and as confirmed by confocal microscopy ex vivo. This establishes that specific alterations of intracellular metabolite diffusion can be measured and related to cell-specific morphological alterations. Furthermore, as reactive astrocytes are a hallmark of many brain pathologies, this work opens exciting perspectives for neuroscience and clinical research.

bioinformatics↗