Dysregulated Neuroimmune and Anhedonia-Like Behavioral Response Following Peripheral Immune Challenge in Mice Carrying the Val66Met Brain-Derived Neurotrophic Factor Polymorphism.

Abstract

Dysregulated inflammatory processes contribute to depression, and gene-environment interactions may influence an individual's risk and resilience. Reduced brain-derived neurotrophic factor (BDNF) expression increases susceptibility for developing depressive symptoms, and the Val66Met (rs6265) single-nucleotide polymorphism (SNP) on the BDNF gene is linked to mood disorders. However, whether Val66Met confers increased vulnerability to inflammation-induced depressive tendencies is unknown. Here, we tested the hypothesis that the Val66Met SNP increases vulnerability to inflammation-induced depressive symptoms in a mouse model of lipopolysaccharide (LPS)-induced depression-like behavior. Behavior and neuroinflammation, following a 24 h LPS challenge, were measured in mice expressing the human BDNF Val66Met gene variant or Val66Val littermates (control). The Val66Met genotype did not affect the peripheral inflammatory response, acute neuroinflammation, or the acute sickness behavior response. Val66Met mice exhibited anhedonia-like behavioral responses following LPS challenge, and we found increased mRNA expression of IL-1β and TNFα in the cerebrum compared to controls. The mRNA expression of IL-1β and TNFα in the hippocampus and the nucleus accumbens of Val66Met mice was increased following LPS, and a significant genotype ×LPS interaction was detected for CD68 expression in the nucleus accumbens. In summary, these data suggest that immune activation in Val66Met mice increased susceptibility to anhedonic behavior and dysregulated negative regulation of inflammation.