Differential effect of repeated lipopolysaccharide treatment and aging on hippocampal function and biomarkers of hippocampal senescence. Differential effect of repeated lipopolysaccharide treatment and aging on hippocampal function and biomarkers of hippocampal senescence

Aging is associated with low-grade chronic systemic inflammation. Elevated peripheral serum cytokines and chemokines contribute to age-related diseases and correlate with cognitive decline. This study compared the effects of repeated lipopolysaccharide (LPS) treatment in young rats to age-related changes in hippocampal-dependent cognition, synaptic transmission, and transcription. Young (5-7 months) Fischer 344 X Brown Norway hybrid rats were injected intraperitoneally once a week for 6-7 weeks with either LPS (1 mg/kg) or vehicle. Older (14-16 months) rats received a similar injection schedule of vehicle. Older-vehicle animals and young-LPS rats exhibited impaired retention of spatial memory. Examination of the transcriptome of the CA1 and the dentate gyrus indicated that older-vehicle and young-LPS animals exhibited an increase in immune response genes. In contrast to aging, young-LPS animals exhibited an increased expression of genes related to the synapse. Even though young-LPS animals increased the expression of synaptic genes, LPS treatment reduced hippocampal CA3-CA1 total synaptic response and N-methyl-D-aspartate receptor (NMDAR)-mediated component of the synaptic response. Interestingly, the decrease in NMDAR function was not redox-sensitive. This study demonstrates that repeated exposure to LPS has long-term effects on hippocampal synaptic transmission and memory; however, young animals exhibited transcriptional recovery after LPS treatment. Recovery likely results from the acute nature of repeated LPS injections, relative to chronic systemic inflammation observed during aging. Overall design: RNA-sequencing was performed on the hippocampal subregions CA1 and DG from young-vehicle (n=8), young-LPS (n=8), and old-vehicle (n=6) animals. Three different comparisons were made treatment (young-LPS v young-vehicle), age (aged-vehicle v young-vehicle), and young-LPS v aged-vehicle. The final comparison was performed to determine the similarities/differences between the effect of peripheral inflammation and age on the hippocampal transcriptome.