A role for NMDA-receptor channels in working memory

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Abstract

The NMDA class of glutamate receptors has a critical role in the induction of long-term potentiation (LTP), a synaptic modification that may encode some forms of long-term memory. However, NMDA-receptor antagonists disrupt a variety of mental processes1,2,3,4,5,6 that are not dependent on long-term memory. For example, they interfere with working memory1,6, a short-lasting form of memory that is maintained by neuronal activity7 rather than by synaptic modification. This suggests that there are unknown functions of the NMDA-receptor channel. One hint is that in addition to producing the calcium entry important for LTP induction, NMDA-receptor channels produce voltage-dependent excitatory postsynaptic potentials (EPSPs)8. Here, we use a network model to show that such NMDA-receptor-mediated EPSPs could be critical in maintaining working memory. These results provide a mechanistic framework useful in understanding dopamine-NMDA interactions in working memory and the disruption of working memory in schizophrenia.

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Figure 1: Maintenance of working memory by NMDA-receptor-mediated synaptic transmission at recurrent synapses.
Figure 2: Properties of network storage of working memory.

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Acknowledgements

The authors thank Patricia Goldman-Rakic, Amy Arnsten, John Krystal, Charles Yang, Matthew Shapiro, Eve Marder and Larry Abbott for comments on the manuscript and Bita Moghaddam, D. Javitt and R. Greene for helpful discussions. The authors gratefully acknowledge the support of the W.M. Keck Foundation. This work was supported by the National Science Foundation, the Office of Naval Research, the National Alliance for Research on Schizophrenia and Depression, and the Alfred P. Sloan Foundation.

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Correspondence to John E. Lisman.

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