Figure 10.
Proposed model for the mechanisms involved in impairment of spatial learning and memory in rats with HE and for their improvement by infliximab. (A) Peripheral inflammation in PCS rats results in increased nuclear content of NF-kB in hippocampus which induces the transcription of pro-inflammatory TNF-a and IL-1b, which activate their receptors in neurons of hippocampus. This leads to translocation of AMPA and NMDA receptors. Membrane expression of GluR1 subunit is reduced that of GluR2 increased. For NMDA receptors NR1 is reduced and NR2A increased in membrane in PCS rats. This altered expression of glutamate receptors results in altered neurotransmission which, in turn, leads to impaired spatial learning and memory in the Radial and Morris water mazes. (B) Treatment with infliximab reduces peripheral inflammation and p50 subunit of NF-kB content in the nucleus, which is translocated to nucleoli. NF-kB in the nucleoli can't activate transcription of TNF-a and IL-1b, resulting in reduced neuroinflammation in PCS rats treated with infliximab. This reduces activation of TNF-a and IL-1b receptors in the neurons and normalizes membrane expression of AMPA receptors. Normalization of neurotransmission leads to restoration of spatial learning and memory.