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The Journal of Neuroscience, September 1, 1998, 18(17):6704-6712

Increased Thresholds for Long-Term Potentiation and Contextual Learning in Mice Lacking the NMDA-type Glutamate Receptor 1 Subunit

Yuji Kiyama¹, Toshiya Manabe², Kenji Sakimura^{3, 4}, Fumiko Kawakami², Hisashi Mori¹, and Masayoshi Mishina^{1, 4}

Departments of ¹ Molecular Neurobiology and Pharmacology and ² Neurophysiology, School of Medicine, University of Tokyo, Tokyo 113-0033, Japan, ³ Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan, and ⁴ Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan

The NMDA-type glutamate receptor (GluR) channel, composed of the GluR and GluR subunits, plays a key role in synaptic plasticity in the CNS. The mutant mice lacking the GluR1 subunit exhibited a reduction in hippocampal long-term potentiation (LTP), but a stronger tetanic stimulation restored the impairment and the saturation level of LTP was unaltered. These results suggest an increase of threshold for LTP induction in the GluR1 mutant mice. After a series of backcrosses we established a GluR1 mutant mouse line with a 99.99% pure C57BL/6 genetic background. The performance of the mutant mice in tone- and context-dependent fear conditioning tests was comparable with that of the wild-type mice. However, a significant difference in the extent of contextual learning became apparent when the chamber exposure time before footshock was shortened. Furthermore, there was a significant difference in freezing responses immediately after footshock on the conditioning day between the wild-type and mutant mice, and the difference was not restored by longer chamber exposure in contrast to the contextual learning on the next day of the conditioning. These results suggest that the GluR1 subunit of the NMDA receptor channel is a determinant of thresholds for both hippocampal LTP and contextual learning and plays differential roles in two forms of contextual fear memories.

Key words: NMDA receptor channel; GluR1 subunit; contextual learning; fear conditioning; LTP; threshold; memory; hippocampus

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18176704-09$05.00/0

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