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Published on: February 26, 2012
Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility
Russell E Nicholls1, Juan Marcos Alarcon, Gaël Malleret
1Center for Neurobiology & Behavior, Columbia University, New York, NY 10032, USA.
Abstract:
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.
Insights
Long-term depression (LTD) is crucial for behavioral flexibility. Inhibiting protein phosphatase 2A in mice impaired NMDAR-dependent LTD, hindering their ability to adapt to new learning tasks.
Area of Science:
- Neuroscience
- Molecular Biology
- Behavioral Science
Background:
- Long-term potentiation (LTP) is widely studied for its role in learning and memory.
- The function of long-term depression (LTD) in cognitive processes remains less understood.
- Protein phosphatase 2A (PP2A) is a key enzyme implicated in synaptic plasticity.
Purpose of the Study:
- To investigate the role of NMDAR-dependent LTD in learning and memory.
- To determine if inhibiting PP2A affects LTD and subsequent cognitive functions.
- To explore the necessity of LTD for behavioral flexibility.
Main Methods:
- Generated transgenic mice expressing SV40 small t antigen to inhibit PP2A.
- Assessed NMDAR-dependent LTD at Schaffer collateral synapses.
- Evaluated behavioral flexibility using the Morris water maze and a delayed nonmatch to place T-maze task.
Main Results:
- Small t antigen expression successfully blocked stimulus-induced and chemically induced NMDAR-dependent LTD.
- Synaptic potentiation, depotentiation, and mGluR-dependent LTD remained unaffected.
- Mice exhibited significant deficits in behavioral flexibility in both maze tasks.
Conclusions:
- NMDAR-dependent LTD is essential for behavioral flexibility.
- Inhibition of PP2A disrupts NMDAR-dependent LTD, leading to cognitive deficits.
- LTD may facilitate learning by weakening irrelevant memory traces during new information acquisition.
