Biology subjects

Agulhon, C.

Publications and source records attributed to Agulhon, C..

4 recordsLinked to original sources

bioRxiv2024

Satellite glial cells modulate proprioceptive neuron activity in dorsal root ganglia

Proprioception, the sense of body and limb position, is mediated by proprioceptors and is crucial for important motor functions such as standing and walking. Proprioceptor cell bodies reside within the peripheral dorsal root ganglia (DRG) and are tightly enveloped by satellite glial cells (SGCs). SCGs express a number of Gq protein-coupled receptors (Gq GPCRs), but their functional consequences on proprioceptor activity is unknown. Using a combination of chemogenetics, genetics, Ca2+ imaging, pharmacology, immunohistochemistry, and biochemistry, we provide evidence that SGC Gq GPCR signaling is sufficient to drive purinergic receptor-mediated Ca2+ responses in proprioceptor cell bodies. Our findings suggest a potential role for SGC Gq GPCR signaling in shaping proprioceptor information processing. Furthermore, this demonstration of SGC-induced proprioceptor activation has profound implications with SGC Gq GPCR signaling and purinergic receptors representing potential therapeutic targets for alleviating some proprioceptor and sensorimotor impairments associated with spinal muscular atrophy or Friedreichs ataxia.

neuroscience↗

bioRxiv2024

Chronic activation of astrocytic Gq GPCR signaling has causal effects on visual LTP formation: implications for neurodegenerative diseases

Astrocytes are the most abundant glial cells in the central nervous system and interact with other cell types, including neurons and microglia, via Gq protein-coupled receptors (Gq GPCRs) present on their surface. Astrocytic Gq GPCR activation induces Ca2+ release from internal stores, leading to intracellular Ca2+ elevations. There is emerging evidence supporting that astrocytic Gq GPCR Ca2+ elevations are upregulated and dysregulated in neurodegenerative diseases and are thought to play an important role in the pathogenesis of such diseases. Furthermore, astrocytic Gq GPCR Ca2+-dependent release of neuroactive or inflammatory molecules from astrocytes may occur in the early steps of the stress/inflammatory process in the diseased brain. In addition, low grade and chronic brain inflammation is involved in the etiology of neurodegenerative diseases. We hypothesized that chronic activation of astrocytic Gq GPCR Ca2+ signaling leads to an altered production of glutamate or pro-inflammatory factors from astrocytes, and consequent deficits in synaptic transmission, long-term potentiation (LTP), and memory formation. To test this hypothesis, we used an AAV-based chemogenetic tool to selectively activate astrocyte Gq GPCR Ca2+ signaling combined with in vivo electrophysiology, immunohistochemistry, and biochemistry. Using the mouse primary visual cortex (V1) as a model system, we found that chronically increased astrocytic Gq GPCR Ca2+ signaling leads to a decrease in LTP of visual-evoked potentials. Such LTP impairment was associated with microglial reactive phenotype - displaying a hyper-ramified and proliferative state - as well as a decrease in the number of interleukin 33 (IL-33)-expressing astrocytes. Our study is the first to have shown that chronic astrocytic Gq GPCR activation is sufficient to alter visual LTP and induce astrocyte-to-microglia communication, possibly through and IL-33 pathway in the adult brain. Because GPCRs are important drug targets, our study could have relevant therapeutic implications in the treatment of some neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Frataxin deficiency in proprioceptive neurons is causal to inflammatory and glial responses in dorsal root ganglia

Friedreich ataxia (FA), the most common recessive hereditary ataxia, is an early-onset neurodegenerative disease characterized by pathological changes occurring first in the peripheral dorsal root ganglia (DRG), with loss of the large sensory proprioceptive neurons, leading to ganglionopathy and proprioceptive deficits. FA is caused by a mutation in frataxin gene (Fxn), leading to reduced expression of frataxin protein (FXN), an essential ubiquitous mitochondrial protein. Most research has focused on the pathophysiological involvement of proprioceptors. However, in recent years, neuroinflammation is increasingly recognized as an integral and critical contributor in FA pathogenesis. Furthermore, it has also recently been shown a primary reactivity of satellite glial cells (SGCs; glia tightly enwrapping proprioceptor cell bodies), suggesting a role of inflammation and SGC responses in the destruction of proprioceptors in FA patients DRGs. It remains unclear to what extent the increase in DRG macrophage response and/or SGC reactivity may contribute to FA phenotype. Therefore, it is important to fully study and understand the mechanism of proprioceptor-macrophages-SGC interactions and their regulations. Exploring relationship between these three cell types has profound implications for breaking through the limitation of treatment of FA. Here we asked whether FXN deficiency selectively in DRG proprioceptive neurons is sufficient to cause inflammatory and glial responses found in patients DRG. We used RNA profiling, bioinformatics signaling network and pathway analysis, combined with immunohistochemistry and behavioral experiments to reveal some genes, signaling pathways in macrophages and SGCs that may represent potential biomarkers of the disease. Our study revealed that proprioceptor FXN deficiency causes major changes in inflammatory macrophage and SGC gene transcription as well as macrophage and SGC number, highlighting molecular and cellular pathways that were sequentially altered, thus representing temporal signatures of FA ganglionopathy progression.

neuroscience↗

bioRxiv2020

Characterization of transgenic mouse lines for selectively targeting glial cells in dorsal root ganglia

The importance of glial cells in the modulation of neuronal processes is now generally accepted. In particular, enormous progress in our understanding of astrocytes and microglia physiology in the central nervous system (CNS) has been made in recent years, due to the development of genetic and molecular toolkits. However, the roles of satellite glial cells (SGCs) and macrophages - the peripheral counterparts of astrocytes and microglia - remain poorly studied despite their involvement in debilitating conditions, such as pain. Here, we characterized in dorsal root ganglia (DRGs), different genetically-modified mouse lines previously used for studying astrocytes and microglia, with the goal to implement them for investigating DRG SGC and macrophage functions. Although SGCs and astrocytes share some molecular properties, most tested transgenic lines were found to not be suitable for studying selectively a large number of SGCs within DRGs. Nevertheless, we identified and validated two mouse lines: (i) a CreERT2 recombinase-based mouse line allowing transgene expression almost exclusively in SGCs and in the vast majority of SGCs, and (ii) a GFP-expressing line allowing the selective visualization of macrophages. In conclusion, among the tools available for exploring astrocyte functions, a few can be used for studying selectively a great proportion of SGCs. Thus, efforts remain to be made to characterize other available mouse lines as well as to develop, rigorously characterize and validate new molecular tools to investigate the roles of DRG SGCs, but also macrophages, in health and disease.

neuroscience↗