Abstract
BackgroundNumerous neurological and psychiatric disorders show sex differences in incidence, age of onset, symptomatology or outcome. Astrocytes, one of the glial cell types of the brain, show sex differences in number, differentiation and function. Since astrocytes are involved in the response of neural tissue to injury and inflammation, these cells may participate in the generation of sex differences in the response of the brain to pathological insults. To explore this hypothesis, we have examined whether male and female astrocytes show a different response to an inflammatory challenge and whether perinatal testosterone influences this response.MethodsCortical astrocyte cultures were prepared from postnatal day 1 (one day after birth) male or female CD1 mice pups. In addition, cortical astrocyte cultures were also prepared from female pups that were injected at birth with 100 μg of testosterone propionate or vehicle. Cultures were treated for 5 hours with medium containing lipopolysaccharide (LPS) or with control medium. The mRNA levels of IL6, interferon-inducible protein 10 (IP10), TNFα, IL1β, Toll-like receptor 4 (TLR4), steroidogenic acute regulatory protein and translocator protein were assessed by quantitative real-time polymerase chain reaction. Statistical significance was assessed by unpaired t-test or by one-way analysis of variance followed by the Tukey post hoc test.ResultsThe mRNA levels of IL6, TNFα and IL1β after LPS treatment were significantly higher in astrocytes derived from male or androgenized females compared to astrocytes derived from control or vehicle-injected females. In contrast, IP10 mRNA levels after LPS treatment were higher in astrocytes derived from control or vehicle-injected females than in those obtained from males or androgenized females. The different response of male and female astrocytes to LPS was due neither to differences in the basal expression of the inflammatory molecules nor to differences in the expression of the LPS receptor TLR4. In contrast, the different inflammatory response was associated with increased mRNA levels of translocator protein, a key steroidogenic regulator, in female astrocytes that were treated with LPS.ConclusionsMale and female cortical astrocytes respond differentially to an inflammatory challenge and this may be predetermined by perinatal testosterone exposure.
Highlights
Numerous neurological and psychiatric disorders show sex differences in incidence, age of onset, symptomatology or outcome
The results indicate that, under basal conditions, cultures obtained from postnatal day 1 (PND1) male and female pups expressed similar mRNA levels of these cytokines (Figure 1)
Astrocytes from control and androgenized females expressed different mRNA levels of IL6, inducible protein 10 (IP10), TNFa and IL1b after LPS exposure To explore the basis of the sex differences detected in the previous experiment, we obtained astrocyte cultures from females treated 24 hours earlier, on PND0, with testosterone propionate and from control females injected on PND0 with vehicle
Summary
Numerous neurological and psychiatric disorders show sex differences in incidence, age of onset, symptomatology or outcome. Since astrocytes are involved in the response of neural tissue to injury and inflammation, these cells may participate in the generation of sex differences in the response of the brain to pathological insults. To explore this hypothesis, we have examined whether male and female astrocytes show a different response to an inflammatory challenge and whether perinatal testosterone influences this response. It is plausible that sex differences in astrocytes might be involved in the generation of sex differences in the manifestation of brain pathological alterations In this regard, previous studies have shown that cortical astrocytes from male mice are less resistant than those from female mice to oxygenglucose deprivation [32]. Since aromatase activity is neuroprotective [33,34], the sexually dimorphic activity of the enzyme in astrocytes may contribute to protect these cells and other CNS cell types, including neurons, from damage
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