Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility

Neuron. 2008 Apr 10;58(1):104-17. doi: 10.1016/j.neuron.2008.01.039.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Psychological / physiology
  • Animals
  • Behavior, Animal / physiology
  • HeLa Cells
  • Humans
  • Long-Term Synaptic Depression / genetics*
  • Male
  • Maze Learning / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Rats
  • Receptors, N-Methyl-D-Aspartate / deficiency*
  • Receptors, N-Methyl-D-Aspartate / genetics*
  • Receptors, N-Methyl-D-Aspartate / physiology


  • Receptors, N-Methyl-D-Aspartate