Tumor necrosis factor alpha (TNF-α) is a vital component of the immune system and CNS. We previously showed that 3-month-old TNF-α and TNF-α receptor knockout mice had impaired cognition, whilst at 12-months-old mice had better cognition. To extend these findings on possible age-dependent TNF-α effects in the brain, we investigated the behaviour of 6-month-old TNF-α knockout mice and their neurobiological correlates. 6-month-old TNF(-/-), TNF-R1(-/-) and TNF-R2(-/-) mice were compared to age-matched WT mice and tested for various behaviours. ELISA hippocampal levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) and qPCR mRNA levels of Tnfa, Tnfr1, Tnfr2, Il10 and Il1β were measured. TNF-R1(-/-) and TNF(-/-) mice were found to have lesser exploratory behaviour than WT mice, while TNF-R1(-/-) mice displayed better memory than WT and TNF-R2(-/-) mice. Both TNF(-/-) and TNF-R2(-/-) mice exhibited significantly lower immobility on the depression test than WT mice. Additionally, TNF(-/-) mice expressed significantly lower levels of BDNF than WT mice in the hippocampus while TNF-R1(-/-) mice displayed significantly lower BDNF levels compared to both WT and TNF-R2(-/-) mice. TNF-R2(-/-) mice also displayed significantly higher levels of NGF compared to TNF-R1(-/-) mice. These results illustrate that TNF-α and its receptors mediate several behavioural phenotypes. Finally, BDNF and NGF levels appear to be regulated by TNF-α and its receptors even under immunologically unchallenged conditions.