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Originally published in Science Express on 7 June 2007
Science 6 July 2007:
Vol. 317. no. 5834, pp. 94 - 99
DOI: 10.1126/science.1140263
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Research Articles

Dentate Gyrus NMDA Receptors Mediate Rapid Pattern Separation in the Hippocampal Network

Thomas J. McHugh,1,2* Matthew W. Jones,1*{dagger} Jennifer J. Quinn,3{ddagger} Nina Balthasar,4{dagger} Roberto Coppari,4§ Joel K. Elmquist,4§ Bradford B. Lowell,4 Michael S. Fanselow,3 Matthew A. Wilson,1 Susumu Tonegawa1,2||

Forming distinct representations of multiple contexts, places, and episodes is a crucial function of the hippocampus. The dentate gyrus subregion has been suggested to fulfill this role. We have tested this hypothesis by generating and analyzing a mouse strain that lacks the gene encoding the essential subunit of the N-methyl-D-aspartate (NMDA) receptor NR1, specifically in dentate gyrus granule cells. The mutant mice performed normally in contextual fear conditioning, but were impaired in the ability to distinguish two similar contexts. A significant reduction in the context-specific modulation of firing rate was observed in the CA3 pyramidal cells when the mutant mice were transferred from one context to another. These results provide evidence that NMDA receptors in the granule cells of the dentate gyrus play a crucial role in the process of pattern separation.

1 The Picower Institute for Learning and Memory, RIKEN–MIT Neuroscience Research Center, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2 Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3 Department of Psychology, University of California–Los Angeles, Los Angeles, CA 90095, USA.
4 Division of Endocrinology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

* These authors contributed equally to this work.

{dagger} Present address: Department of Physiology, University of Bristol, Bristol BS8 1TD, UK.

{ddagger} Present address: Division of Molecular Psychiatry, Yale University, New Haven, CT 06508, USA.

§ Present address: Center for Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

|| To whom correspondence should be addressed. E-mail: tonegawa{at}mit.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)