Intravenous human interleukin-1 alpha impairs memory processing in mice: Dependence on blood-brain barrier transport into posterior division of the septum

Peripherally administered cytokines profoundly affect the central nervous s ystem (CNS). One mechanism by which they could affect the CNS is by crossin g the blood-brain barrier (BBB) to interact directly with brain receptors. Human and murine IL-1 alpha (hIL-1 alpha; mIL-1 alpha) are transported acro ss the murine BBB with a high rate of transport into the posterior division of the septum (PDS), but it is unknown whether BBB transport is relevant t o their actions. Here, we injected species-specific blocking antibodies int o the PDS to determine whether transport across the BBB is required for blo od-borne hIL-1 alpha to affect memory. Retention was impaired in a dose-dep endent manner when hIL-1 alpha was injected either by tail vein (i.v.) or i nto the PDS, with the PDS route being 1000 times more potent. About 70% of the memory impairment induced by i.v. hIL-1 alpha was reversed by injecting a blocking antibody (Ab) specific for hIL-1 alpha into the PDS. This shows that much of the memory impairment induced by hIL-1 alpha depends on its a bility to cross the BBB. Ab specific for mIL-1 alpha was also effective in reversing memory impairment, showing that hIL-1 alpha releases mIL-1 alpha from endogenous stores. Whether the mIL-1 alpha was released from periphera l stores, which would require it to cross the BBB, or from brain stores is unknown. In conclusion, these results show that exogenous, blood-borne hIL- 1 alpha affects memory by releasing mIL-1 alpha from endogenous stores and by crossing the BBB to act at sites within the PDS.