Interleukin-15 (IL15) is a cytokine produced by normal brain, but the functions of the IL15 system in normal adults are not yet clear. The hypothesis that the hippocampal IL15 system is essential for memory consolidation was tested by use of IL15Ralpha knock-out mice in behavioral, biochemical, immunohistological, and electron microscopic analyses. The knock-out mice showed deficits in memory, determined by the Stone T-maze and fear conditioning. In their hippocampi, the concentration of GABA was significantly lower. There were region-specific changes of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), with increased GAD-67-immunopositive interneurons in the stratum oriens of the CA1 region of the hippocampus, accompanied by nonsignificant reduction of GAD-67 synapses in the CA3 region. Western blotting showed an increase of GAD-65, but not GAD-67, in the hippocampal homogenate. The ultrastructure of the hippocampus remained intact in the knock-out mice. To further test the hypothesis that IL15 directly modulates GABA turnover by reuptake mechanisms, the dose-response relationship of IL15 on (3)H-GABA uptake was determined in two neuronal cell lines. The effective and nontoxic dose was further used in the synaptosomal uptake studies. IL15 decreased the uptake of (3)H-GABA in synaptosomes from the forebrain of wild-type mice. Consistent with this, IL15Ralpha knock-out mice had increased synaptosomal uptake of (3)H-GABA. Overall, the results show novel functions of a unique cytokine in normal hippocampal activity by regulating GABA transmission.