Astrocytic TNFα regulates the behavioral response to antidepressants

Recent studies have suggested that cytokines, and in particular tumor necrosis factor alpha (TNFα), have a role in modulating antidepressant efficacy. To directly test this idea, we compared the response of TNFα−/− mice and astrocyte-specific TNFα−/− mice to the antidepressants fluoxetine and desipramine. Using standard behavior models for measuring antidepressant efficacy, the forced swim test (FST) and tail suspension test (TST), we determined that TNFα−/− mice were essentially normal in basal behavior in the FST and TST. However, TNFα−/− mice showed no behavioral response to a standard dose of chronic antidepressant treatment, in sharp contrast to wildtype mice. Similar results were seen with acute antidepressant treatment, but TNFα−/− mice did respond to a very high-dose acute antidepressant treatment. We also assessed in vitro and in vivo effects of fluoxetine on TNFα expression. Glia responded to serotonin in vitro and fluoxetine in vivo by upregulating TNFα mRNA. Consistent with this source of TNFα, mice with an astrocyte-specific deletion of TNFα also did not respond to standard chronic antidepressant treatment. These data suggest that astrocytic TNFα is important to the sensitivity of the behavioral response to administration of antidepressants.