Biology subjects

Audinat, E.

Publications and source records attributed to Audinat, E..

5 recordsLinked to original sources

bioRxiv2026

Postprandial hypertriglyceridemia activates microglia to promote satiety via an ASC dependent signaling.

Reactive microglia are commonly considered neurotoxic and detrimental for brain functioning. Chronic consumption of a high-fat diet strongly activates microglia, disrupts the central control of energy metabolism, contributes to obesity, and promotes cognitive decline. In this study we report an unexpected beneficial function of microglia reaction at the time scale of a meal, whereby they promote satiety in a macronutrient-dependent manner. We show that murine microglia react to ingested dietary fat within three hours. Specifically, postprandial hypertriglyceridemia induced microglial hyper-ramification alongside with a transcriptional reprogramming promoting communication with neurons. This effect occurs in discrete brain areas, including the hypothalamus and the brainstem, which control hunger. Remarkably, microglia-specific genetic ablation of Apoptosis-associated Speck-like protein containing a CARD (named ASC), a master regulator of metabolism, immune function and cell shape, profoundly alters satiety following high-fat food consumption. These results reveal that microglia engage an immune signaling pathway to rapidly alert the neural circuits and activate an anorectic response that limits overconsumption of dietary fat. Unexpectedly, this regulatory process is sexually dimorphic, present in males only. Furthermore, we found that the postprandial microglial reaction is bypassed during obesity, providing a new therapeutic target to treat maladaptive eating disorders.

neuroscience↗

bioRxiv2026

Long-lasting astrocyte remodeling in Dravet Syndrome Scn1a+/- mouse model.

BackgroundDravet syndrome (DS) is a prototypical developmental and epileptic encephalopathy caused by SCN1A gene mutations leading to NaV1.1 loss of function. The latter causes early-onset drug-resistant seizures and enduring cognitive and behavioral deficits. In this pathological context, the implication of astrocytes remains insufficiently explored. MethodsUsing a heterozygous Scn1a knock-out (Scn1a/-) mouse model that recapitulates the DS-human phenotype, we examine astrocyte remodeling at landmark disease stages, as defined by video-EEG and behavioral read-outs. ResultsFrom initial disease aggravation (PN20-35) to long-term stabilization (up to PN90), Scn1a/- mice showed increased hippocampal and cortical GFAP transcript and protein levels, compared to age-matched control littermates and to an earlier presymptomatic (<PN20) time point. During the aggravation phase in Scn1a/- mice, astrocyte branching, revealed by GFAP histological analysis and by intracellular delivery of Alexa Fluor 488 in hippocampal slices was increased but not sustained long-term. These disease-stage-dependent astrocyte modifications were not associated with macroscopic hippocampal sclerosis or cortical atrophy. To further study astrocyte remodeling during disease progression, we used biocytin diffusion following single-astrocyte loading to reveal an expanded astrocyte-astrocyte network in Scn1a/- mice long-term, along with increased Cx30 and Cx43 protein levels. An ethidium bromide uptake assay indicated impaired astrocytic hemichannel function in Scn1a/- mice long-term. Regionally, these long-term cellular and network astrocyte modifications coincided with augmented post-tetanic synaptic potentiation. DiscussionIn DS, astrocytes undergo a long-lasting network remodeling. We discuss how this astrocyte remodeling may be related to seizures as well as synaptic and cognitive deficits.

neuroscience↗

bioRxiv2020

Restoring Glutamate receptosome dynamics at synapses rescues Autism-like deficits in Shank3-deficient mice.

Shank3 monogenic mutations lead to Autism Spectrum Disorders (ASD). Shank3 is part of the glutamate receptosome that physically links ionotropic NMDA receptors to metabotropic mGlu5 receptors through interactions with scaffolding proteins PSD95-GKAP-Shank3-Homer. A main physiological function of the glutamate receptosome is to control NMDA synaptic function that is required for plasticity induction. Intact glutamate receptosome supports glutamate receptors activation and plasticity induction, while glutamate receptosome disruption blocks receptors activity, preventing the induction of subsequent plasticity. Despite possible impact on metaplasticity and cognitive behaviors, scaffold interaction dynamics and their consequences are poorly defined. Here we used mGlu5-Homer interaction as a biosensor of glutamate receptosome integrity to report changes of NMDA synaptic function. Combining BRET imaging and electrophysiology, we show that a transient neuronal depolarization inducing NMDA-dependent plasticity disrupts glutamate receptosome in a long-lasting manner at synapses and induces signaling required for the expression of the initiated neuronal plasticity such as ERK and mTOR pathways. Glutamate receptosome disruption also decreases NMDA/AMPA currents ratio, freezing the sensitivity of the synapse to subsequent changes of neuronal activity. These data show the importance of a fine-tuning of protein-protein interactions within glutamate receptosome, driven by changes of neuronal activity, to control plasticity. In a mouse model of ASD, a truncated mutant form of Shank3 prevents the integrity of the glutamate receptosome. These mice display altered plasticity, anxiety-like and stereotyped behaviors. Interestingly, repairing the integrity of glutamate receptosome and its sensitivity to the neuronal activity rescued synaptic transmission, plasticity and some behavioral traits of Shank3{triangleup}C mice. Altogether, our findings characterize mechanisms by which Shank3 mutations cause ASD and highlight scaffold dynamics as new therapeutic target.

neuroscience↗

bioRxiv2019

Fat food exacerbates post-prandial hypothalamic inflammation involving GFAP+ cells and microglia

In humans, obesity was associated with brain inflammation and glial cell proliferation. Studies in rodents showed that glial cell proliferation occurs within 24 hours of high-fat diet (HFD) consumption, before obesity development. This proliferation was mainly observed in the hypothalamus (HT), a crucial brain structure for controlling body weight. Therefore, we sought to characterize the post-prandial HT inflammatory response to 1-3-6 hours exposure to a standard diet and HFD. HFD exposure increased gene expression of astrocyte and microglial marker (GFAP and Iba1) compare to standard treated mice and induced morphological modifications of microglial cells in HT. This remodeling was associated with higher expression of inflammatory genes and differential activation of hypothalamic neuropeptides involved in energy balance regulation. DREADD and PLX5622 technologies, used to modulate GFAP-positive or microglial cells activity respectively, showed that both glial cell types are involved in hypothalamic post-prandial inflammation, but in a different time frame and with a diet specificity Thus, an exacerbated post-prandial inflammation in brain might predispose individuals to obesity and needs to be characterized to address this worldwide crisis.

neuroscience↗

bioRxiv2019

Biphasic impact of prenatal inflammation and macrophage depletion on the wiring of neocortical inhibitory circuits

The etiology of neurodevelopmental disorders is linked to defects in Parvalbumin (PV)-expressing cortical interneurons and to prenatal immune challenges. Mouse models of maternal immune activation (MIA) and microglia deficits increase the postnatal density of PV interneurons, raising the question of their functional integration. Here, we show that MIA and embryonic depletion of macrophages including microglia, have a two-step impact on PV interneurons wiring onto their excitatory target neurons in the barrel cortex. In adults, both challenges reduced the inhibitory drive from PV interneurons, as reported in neurodevelopmental disorders. In juveniles, however, we found an increased density of PV neurons, an enhanced strength of unitary connections onto excitatory cells and an aberrant horizontal inhibition with a reduced lateral propagation of sensory inputs in vivo. Our results provide a novel framework for understanding the impact of prenatal immune challenges onto the developmental trajectory of inhibitory circuits that leads to pathological brain wiring.

neuroscience↗