Elsevier

Biological Psychiatry

Volume 59, Issue 9, 1 May 2006, Pages 775-785
Biological Psychiatry

Original article
TNFα Signaling in Depression and Anxiety: Behavioral Consequences of Individual Receptor Targeting

https://doi.org/10.1016/j.biopsych.2005.10.013Get rights and content

Background

Increased serum levels of TNFα and other pro-inflammatory cytokines have been found in patients with major depression and several other psychiatric conditions. In rodents, these cytokines produce symptoms commonly referred to as “sickness behavior.” Some of these, including reduced feeding and decreased social and exploratory behavior, are reminiscent of those seen in depressed patients. Interpretation of these effects is complicated by the malaise caused by acute injections of pro-inflammatory cytokines, however. Thus, it is unclear whether cytokines are involved in the etiology of depressive symptoms.

Methods

We used a panel of behavioral assays to assess TNFR1−/− and TNFR2−/− mice for anxiety and depression-like behaviors.

Results

We show that deletion of either TNFR1 or TNFR2 leads to an antidepressant-like response in the forced swim test and that mice lacking TNFR2 demonstrate a hedonic response in a sucrose drinking test compared with wildtype littermates. In addition, deletion of TNFR1 leads to decreased fear conditioning. There were no differences in behavior in anxiety tests for either null mutant.

Conclusions

These results are consistent with the hypothesis that TNFα can induce depression-like symptoms even in the absence of malaise and demonstrate that both receptor subtypes can be involved in this response.

Section snippets

Mouse Strains and Genotyping

Mice carrying the Tnfrsf1atm1Mak mutation (TNFR1−/−; Pfeffer et al 1993) and Tnfrsf1btm1Mwm (TNFR2−/−; Erickson et al 1994) mutations, respectively, were purchased from the Jackson Laboratory (Bar Harbor, Maine). Both strains have been back-crossed to C57Bl/6 mice for at least 10 generations and were maintained at the Jackson Laboratory by nullXnull sib breedings. Heterozygotes were produced by crosses with wild type C57Bl/6J mice, and these animals were then interbred to produce TNFR1−/− or

Expression of TNFR1 and TNFR2 in the Brain

To verify that TNFR1 and TNFR2 are expressed in brain, we compared mRNA expression levels for the two receptors in five brain regions using real-time PCR analysis (Figure 1). In addition, we tested whether levels of the less abundant receptor, TNFR2, were changed in TNFR1−/− brains. For TNFR1, significant differences were noted between brain regions (F[4,8] = 7.88, p < .01) in TNFR1+/+ mice, with highest expression levels in the brain stem (.658 ± .065) and lowest levels in the cerebellum (.250

Discussion

We examined the expression profiles of TNFR1 and TNFR2 in five major brain regions. The expression of TNFR1 varied among the regions, but both receptors were found throughout the brain. Overall, the level of TNFR1 was approximately 2.5-fold higher than that of TNFR2. These results are consistent with the report that TNFR1 and 2 are constitutively expressed by microglia, whereas astrocytes and oligodendrocytes only express TNFR1 (Dopp et al 1997). The high expression of TNFR1 in the brain stem

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