Abstract

Peripherally administered cytokines profoundly affect the central nervous system (CNS). One mechanism by which they could affect the CNS is by crossing the blood-brain barrier (BBB) to interact directly with brain receptors. Human and murine IL-1α (hIL-1α; mIL-1α) are transported across 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 to their actions. Here, we injected species-specific blocking antibodies into the PDS to determine whether transport across the BBB is required for blood-borne hIL-1α to affect memory. Retention was impaired in a dose-dependent manner when hIL-1α was injected either by tail vein (i.v.) or into the PDS, with the PDS route being 1000 times more potent. About 70% of the memory impairment induced by i.v. hIL-1α was reversed by injecting a blocking antibody (Ab) specific for hIL-1α into the PDS. This shows that much of the memory impairment induced by hIL-1α depends on its ability to cross the BBB. Ab specific for mIL-1α was also effective in reversing memory impairment, showing that hIL-1α releases mIL-1α from endogenous stores. Whether the mIL-1α was released from peripheral 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-1α affects memory by releasing mIL-1α from endogenous stores and by crossing the BBB to act at sites within the PDS.