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The Journal of Neuroscience, June 1, 1998, 18(11):4177-4188

Hippocampal Synaptic Plasticity in Mice Overexpressing an Embryonic Subunit of the NMDA Receptor

Shigeo Okabe¹, Carlos Collin¹, Jonathan M. Auerbach¹, Noam Meiri², Johan Bengzon¹, Mary B. Kennedy³, Menahem Segal⁴, and Ronald D. G. McKay¹

¹ Laboratory of Molecular Biology and ² Laboratory of Adaptive Systems, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, ³ Division of Biology, California Institute of Technology, Pasadena, California 91125, and ⁴ Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel

The effects of changing NMDA receptor subunit composition on synaptic plasticity in the hippocampus were analyzed by creating transgenic mice overexpressing NR2D, a predominantly embryonic NMDA receptor subunit. NMDA-evoked currents in the transgenic mice had smaller amplitudes and slower kinetics. The transgenics also displayed age-dependent deficits in synaptic plasticity in area CA1 of the hippocampus. Long-term depression was selectively impaired in juvenile mice when NR2D overexpression was moderate. In mature mice, overexpression of NR2D was associated with a reduction of both NR2B and Ca²⁺-independent activity of Ca²⁺- and calmodulin-dependent protein kinase II. These biochemical changes were correlated with a marked impairment of NMDA-dependent long-term potentiation, but spatial behavior was normal in these mice. These results show that the developmental regulation of NMDA receptor subunit composition alters the frequency at which modification of synaptic responses occur after afferent stimulation.

Key words: hippocampus; NMDA receptor; long-term potentiation; long-term depression; water maze; transgenic mice

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18114177-12$05.00/0

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