Comparing the role of metabotropic glutamate receptors in long-term potentiation and in learning and memory.

1. Neuronal plasticity has been suggested to be the physical substrate for changes underlying the expression of memory. One model which has attracted wide attention as a possible candidate of such neuronal plasticity is long-term potentiation (LTP), mainly investigated in the hippocampus of rodents. Moreover, various processes with different time constants may underlie LTP, and these phases show striking correspondence to different phases of memory. 2. Pharmacological evidence strongly implicates that the neurotransmitter glutamate plays a major role in LTP. Although the involvement of ionotropic glutamate receptors has been proven, the role of the newly discovered metabotropic glutamate receptors is still uncertain. 3. Metabotropic glutamate receptors (mGluRs) comprise a whole family with currently eight members grouped into three classes according to their amino acid sequence identity and pharmacological profile. They are G-protein coupled, either positively linked to phospholipase C (class I) or negatively linked to adenylate cyclase (class II and III), and among other effects are known to induce phosphorylation of ionotropic glutamate receptors as well as modulate the excitability of neurons. Finally, they are heterogeneously distributed throughout the brain. 4. In hippocampal slice preparations, mGluRs have been shown to be involved in the induction of LTP in CA1 and dentate gyrus by some investigators, but others have failed to reproduce such experiments, leaving the question: what are the appropriate conditions for mGluR-mediated LTP? 5. In vivo, metabotropic receptor antagonists have been shown to block, and agonists to facilitate, induction and maintenance of LTP, mainly at perforant path/dentate granule cell synapses. As demonstrated in behavioral investigations, mGluRs apparently play an important part in hippocampus-dependent learning paradigms. As in LTP, antagonists block memory formation; in contrast to LTP, agonists also prevent memory formation. In memory recall metabotropic receptors seem to play no role. 6. Based on current information the authors develop models for a role of mGluRs in both LTP and memory formation. Activation of metabotropic receptors plays a particular modulatory role when high frequency stimulation is weak. Strong tetanization may bypass mGluRs by stimulating other systems leading to, at least phenomenologically, similar LTP, Behaviorally, mGluRs possibly set the signal to noise ratio of the hippocampal circuit.