While most studies have focused on the role of long-term potentiation in behavior, far less is known about the role of long-term depression (LTD). To examine the potential involvement of LTD in learning and memory, we generated transgenic mice that express a fragment of the SV40 small t antigen known to inhibit protein phosphatase 2A (PP2A). Small t antigen expression blocked both stimulus-induced and chemically induced NMDAR-dependent LTD at Schaffer collateral synapses but did not affect potentiation, depotentiation, or mGluR-dependent LTD. This physiological phenotype was associated with deficits in behavioral flexibility in both the Morris water maze and a delayed nonmatch to place T-maze task, suggesting that NMDAR-dependent LTD is required for behavioral flexibility and may act by weakening previously encoded memory traces when new information is learned.
