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Volume 17, Number 13, Issue of July 1, 1997 pp. 5196-5205
Copyright ©1997 Society for Neuroscience

Mice Lacking Metabotropic Glutamate Receptor 5 Show Impaired Learning and Reduced CA1 Long-Term Potentiation (LTP) But Normal CA3 LTP

Received Nov. 11, 1996; revised April 8, 1997; accepted April 11, 1997.

You-Ming Lu1, Zhengping Jia1, Christopher Janus1, Jeffrey T. Henderson1, Robert Gerlai1, J. Martin Wojtowicz2, and John C. Roder1

1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada, and 2 Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Class I metabotropic glutamate receptors (mGluRs) have been postulated to play a role in synaptic plasticity. To test the involvement of one member of this class, we have recently generated mutant mice that express no mGluR5 but normal levels of other glutamate receptors. The CNS revealed normal development of gross anatomical features. To examine synaptic functions we measured evoked field EPSPs in the hippocampal slice. Measures of presynaptic function, such as paired pulse facilitation in mutant CA1 neurons, were normal. The response of mutant CA1 neurons to low concentrations of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) was missing, which suggests that mGluR5 may be the primary high affinity ACPD receptor in these neurons. Long-term potentiation (LTP) in mGluR5 mutants was significantly reduced in the NMDA receptor (NMDAR)-dependent pathways such as the CA1 region and dentate gyrus of the hippocampus, whereas LTP remained intact in the mossy fiber synapses on the CA3 region, an NMDAR-independent pathway. Some of the difference in CA1 LTP could lie at the level of expression, because the reduction of LTP in the mutants was no longer observed 20 min after tetanus in the presence of 2-amino-5-phosphonopentanoate. We propose that mGluR5 plays a key regulatory role in NMDAR-dependent LTP. These mutant mice were also impaired in the acquisition and use of spatial information in both the Morris water maze and contextual information in the fear-conditioning test. This is consistent with the hypothesis that LTP in the CA1 region may underlie spatial learning and memory.

Key words: hippocampus; gene targeting; long-term potentiation; metabotropic glutamate receptor 5; spatial learning; snyaptic function




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