Dysfunction of the BDNF-TrkB signaling pathway contributes to learning and memory impairments induced by neuroinflammation in mice

Background and Purpose: Evidence suggests neuroinflammation is the main mechanism in cognitive dysfunction. The brain-derived neurotrophic factor (BDNF) is involved in learning and memory via binding to tyrosine kinase B (TrkB) receptors. Herein, we mainly tested roles of the BDNF-TrkB signaling pathway and its downstream cascades in lipopolysaccharide (LPS) induced cognitive dysfunction in mice. Experimental Approach: Mice were treated with LPS and 7,8-DHF for 7 days, and learning and memory function was evaluated by the novel object recognition test (NORT). Western blot and enzyme-linked immunosorbent assay (ELISA) elucidated roles of the BDNF-TrkB signaling pathway and its downstream cascades in LPS mice. Key Results: The NORT showed that LPS induced learning and memory deficits in mice. LPS increased the levels of IL-1β, IL-6, and TNF-α in the serum of mice. In the hippocampus and mPFC regions, LPS reduced protein levels of BDNF, p-TrkB, Bcl-2, p-ERK1/2, p-CaMK2, p-CREB and p-GluR1 and increased the expression of Bax. In the EC, levels of BDNF, p-TrkB, Bcl-2, p-CaMK2 and p-CREB proteins were reduced and the protein level of Bax was increased in LPS mice. 7,8-DHF could alleviate these disorders in LPS mice and improved their learning and memory function, however, the TrkB antagonist ANA12 effectively reversed the effects of 7,8-DHF. Conclusion and Implications: These results revealed that the BDNF-TrkB signaling pathway and its downstream cascades disorders contributed to neuroinflammation induced cognitive dysfunction in mice. 7,8-DHF could become a new therapeutic drug for cognitive dysfunction induced by BDNF-TrkB signaling pathway disorders in neurodegenerative diseases.