MICE LACKING THE GENE ENCODING TISSUE-TYPE PLASMINOGEN-ACTIVATOR SHOWA SELECTIVE INTERFERENCE WITH LATE-PHASE LONG-TERM POTENTIATION IN BOTH SCHAFFER COLLATERAL AND MOSSY FIBER PATHWAYS

The gene encoding tissue-type plasminogen activator (t-PA) is an immed iate response gene, downstream from CREB-1 and other constitutively ex pressed transcription factors, which is induced in the hippocampus dur ing the late phase of long-term potentiation (L-LTP). Mice in which th e t-PA gene has been ablated (t-PA(-/-)) showed no gross anatomical, e lectrophysiological, sensory, or motor abnormalities but manifest a se lective reduction in L-LTP in hippocampal slices in both the Schaffer collateral-CA1 and messy fiber-CA3 pathways, t-PA(-/-) mice also exhib it reduced potentiation by cAMP analogs and D1/D5 agonists. By contras t, hippocampal-dependent learning and memory were not affected in thes e mice, whereas performance was impaired on two-way active avoidance, a striatum-dependent task. These results provide genetic evidence that t-PA is a downstream effector gene important for L-LTP and show that modest impairment of L-LTP in CA1 and CA3 does not result in hippocamp us-dependent behavioral phenotypes.