MICE LACKING METABOTROPIC GLUTAMATE-RECEPTOR-5 SHOW IMPAIRED LEARNINGAND REDUCED CA1 LONG-TERM POTENTIATION (LTP) BUT NORMAL CA3 LTP

Class 1 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 exp ress 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 s lice. Measures of presynaptic function, such as paired pulse facilitat ion in mutant CA1 neurons, were normal, The response of mutant CA1 neu rons to low concentrations of (1S,3R)-1-amino-cyclopentane-1,3-dicarbo xylic acid (ACPD) was missing, which suggests that mGluR5 may be the p rimary high affinity ACPD receptor in these neurons, Long-term potenti ation (LTP) in mGluR5 mutants was significantly reduced in the NMDA re ceptor (NMDAR)-dependent pathways such as the CA1 region and dentate g yrus of the hippocampus, whereas LTP remained intact in the messy fibe r synapses on the CA3 region, an NNtDAR-independent pathway. Some of t he 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 aft er tetanus in the presence of 2-amino-5-phosphonopentanoate . We propo se that mGluR5 plays a key regulatory role in NMDAR-dependent LTP. The se mutant mice were also impaired in the acquisition and use of spatia l 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.