Gene targeting reveals a role for the glutamate receptors mGluR5 and GluR2 in learning and memory.

This work suggests that class I mGluRs are involved in long-term potentiation (LTP) at CA1 synapses within the hippocampus. Our data support a pathway linking class I-mGluRs with PKC and src to enhance the open probability of the NMDAR channel. This leads to LTP of the NMDAR, but not the AMPAR. We are currently analyzing double mGluR1 X mGluR5 knockouts with Collingridge for a loss of the LTP induction switch [Nature 368 (1994) 740.]. This induction of LTP of the NMDAR is necessary for "spatial" learning and memory to occur, since mice lacking the mGluR5 are deficient in the Morris water maze and context-dependent fear conditioning. We postulate that AMPARs may provide negative feedback inhibition to the NMDAR. Hence, in null mutants lacking the AMPAR subtype, GluR2, LTP in the CA1 region of hippocampal slices was markedly enhanced (twofold) and non-saturating, whereas neuronal excitability and paired-pulse facilitation were normal. The ninefold increase in Ca(2+) permeability, in response to kainate application, suggests one possible mechanism for enhanced LTP. Enhanced LTP could result from enhanced AMPAR channel conductance or increased recruiting of previously silent synapses. Since the GluR2 null mutants showed reduced exploration and impaired motor coordination, we could make no conclusion about its role in learning and memory. Future work will be directed to inducible deletion of GluR2 only in CA1 after development is complete. These results support the correlation between LTP and learning and memory.