Conclusions
These findings indicate that the cognitive decline observed in DIO mice is due, in part, to reduced fractalkine-CX3CR1 signaling in the corticolimbic system.
Methods
Mice were given 60% high-fat diet for 16 weeks. The expression of fractalkine and CX3CR1 in the hippocampus, amygdala and prefrontal cortex of DIO mice was analyzed. Cognitive ability in the Y-maze test and hippocampal glutamate receptors and synaptic markers were observed in DIO and CX3CR1 antagonist-treated mice. Regulation of fractalkine and CX3CR1 expression in the hippocampus was examined following administration of a selective insulin-like growth factor-1 (IGF-1) receptor inhibitor and a tyrosine receptor kinase B (TrkB) antagonist in normal mice.
Results
DIO mice exhibited significant cognitive deficits in the Y-maze test and decrease in fractalkine and CX3CR1 in the hippocampus and amygdala compared with mice fed a control diet (CD mice). Administration of the CX3CR1 antagonist 18a in normal mice induced significant cognitive deficits in the Y-maze test. DIO mice and CX3CR1 antagonist-treated mice exhibited significant decreases in protein levels of NMDA (N-methyl-D-aspartate) receptor subunit (NR2A), AMPA (α-amino-5-methyl-3-hydroxy-4-isoxazole propionate) receptor subunit (GluR1) and postsynaptic density protein 95 in the hippocampus compared with their respective controls. Furthermore, plasma IGF-1 and hippocampal brain-derived neurotrophic factor were significantly decreased in DIO mice compared with CD mice. Administration of a selective IGF-1 receptor inhibitor and a TrkB antagonist in normal mice significantly decreased fractalkine and CX3CR1 in the hippocampus. Conclusions: These findings indicate that the cognitive decline observed in DIO mice is due, in part, to reduced fractalkine-CX3CR1 signaling in the corticolimbic system.