Madore-Delpech, C. | Search bioRxiv

bioRxiv2025

Sex specific correction of maternal inflammation-induced behavioral abnormalities by the inhibition of colony-stimulating factor 1 receptor

We have previously reported the therapeutic effect of depletion and regeneration of endogenous microglia on autism spectrum disorder-like behaviors in offspring from the dams under maternal immune activation (MIA) by dampening their neuritogenic activation. Here we show a long-lasting pathological effect by MIA, leading to abnormal behaviors in offspring mice in a sex-specific manner at 3 months of age. MIA was induced by injecting Polyinosinic:polycytidylic acid [Poly(I:C)] at 10mg/kg at E9.5 with preselected dams based on the immunoreactivity to low-dose Poly(I:C) injection. MIA offspring show impairments in sociability, repetitive behavior, and spatial working and associative memories in both sexes, whereas only male offspring show social novelty deficit. MIA has no effect on anxiety-like behavior nor sensori-motor or locomotor activity. Administering colony stimulating factor receptor (CSF1R) inhibitor in young adult MIA offspring regenerates microglia and ameliorates sociability deficits in males and spatial working and associative memory impairments in both sexes without effect on social novelty impairments. Transcriptomic analysis of prefrontal cortex and hippocampal tissues reveals MIA and sex-specific pathways and highlights potential key genes involved in the corrective effect of microglial regeneration in MIA offspring. Our results underscore the potential of the sex-specific therapeutic applications of CSF1R inhibitor for MIA-related social and cognitive disorders.

animal behavior and cognition↗

bioRxiv2023

Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS

Adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral tissues. ATGL has been associated with both pro- and anti-inflammatory responses in different tissues suggesting its actions are dependent on cell type. Recent studies in microglia and macrophages suggest that lipid droplets (LD), a triglyceride storing organelle, and LD lipolysis via ATGL are important components of inflammatory responses. Here, we determined the impact of ATGL inhibition and microglia-specific ATGL loss-of-function on inflammatory and behavioural responses to acute pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines in mouse primary microglia cultures. LPS led to LD accumulation in microglia and altered the expression of lipolysis regulators. The pan-lipase inhibitor ORlistat alleviated LPS-induced expression of IL-1{beta} and IL-6. Specific inhibition of ATGL by ATGListatin had similar anti-inflammatory action on cytokines expression and secretion in both neonatal and adult microglia cultures. Second, targeted and untargeted lipidomic studies revealed that ATGL inhibition reduced LPS-induced generation of pro-inflammatory prostanoids and affected ceramide profile. Finally, the role of ATGL in neuroinflammation was assessed in a novel mouse model with inducible ATGL deletion specifically in microglia. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and reduced LPS-induced sickness behaviour. Together, our results demonstrate that pharmacological inhibition or loss of ATGL-mediated triglyceride lipolysis reduces LPS-induced inflammation to suggest that inhibition of lipolysis plays a beneficial role in neuroinflammation.

neuroscience↗