Gene targeting reveals a role for the glutamate receptors mGluR5 and GluR2in learning and memory

This work suggests that class I mGluRs are involved in long-term potentiati on (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 a re currently analyzing double mGluR1 X mGluR5 knockouts with Collingridge f or a loss of the LTP induction switch [Nature 368 (1994) 740.]. This induct ion of LTP of the NMDAR is necessary for "spatial" learning and memory to o ccur, since mice lacking the mGluR5 are deficient in the Morris water maze and context-dependent fear conditioning. We postulate that AMPARs may provi de negative feedback inhibition to the NMDAR. Hence, in null mutants lackin g the AMPAR subtype, GluR2, UP in the CA1 region of hippocampal slices was markedly enhanced (twofold) and non-saturating, whereas neuronal excitabili ty and paired-pulse facilitation were normal. The ninefold increase in Ca2 permeability, in response to kainate application, suggests one possible me chanism for enhanced LTP. Enhanced LTP could result from enhanced AMPAR cha nnel conductance or increased recruiting of previously silent synapses. Sin ce the GluR2 null mutants showed reduced exploration and impaired motor coo rdination, we could make no conclusion about its role in learning and memor y. Future work will be directed to inducible deletion of GluR2 only in CA1 after development is complete. These results support the correlation betwee n LTP and learning and memory. (C) 2001 Elsevier Science Inc. All rights re served.