TNF-a and its receptors modulate complex behaviours and neurotrophins in transgenic mice

Summary: Tumour necrosis factor-α (TNF-α) plays an important role not only in immunity but also in the normal functioning of the central nervous system (CNS). At physiological levels, studies have shown TNF-α is essential to maintain synaptic scaling and thus influence learning and memory formation while also playing a role in modulating pathological states of anxiety and depression. TNF-α signals mainly through its two receptors, TNF-R1 and TNF-R2, however the exact role that these receptors play in TNF-α mediated behavioural phenotypes is yet to be determined. Methods: We have assessed TNF−/−, TNF-R1−/− and TNF-R2−/− mice against C57BL/6 wild-type (WT) mice from 12 weeks of age in order to evaluate measures of spatial memory and learning in the Barnes maze (BM) and Y-maze, as well as other behaviours such as exploration, social interaction, anxiety and depression-like behaviour in a battery of tests. We have also measured hippocampal and prefrontal cortex levels of the neurotrophins nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) as well as used immunohistochemical analyses to measure number of proliferating cells (Ki67) and immature neurons (DCX) within the dentate gyrus. Results: We have shown that young adult TNF−/− and TNF-R1−/− mice displayed impairments in learning and memory in the BM and Y-maze, while TNF-R2−/− mice showed good memory but slow learning in these tests. TNF−/−and TNF-R2−/− mice also demonstrated a decrease in anxiety like behaviour compared to WT mice. ELISA analyses showed TNF−/− and TNF-R2−/− mice had lower levels of NGF compared to WT mice. Conclusion: These results indicate that while lack of TNF-α can decrease anxiety-like behaviour in mice, certain basal levels of TNF-α are required for the development of normal cognition. Furthermore our results suggest that both TNF-R1 and TNF-R2 signalling play a role in normal CNS function, with knockout of either receptor impairing cognition on the Barnes maze