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

Abstract

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)Ϫ1-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.

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

“…This is consistent with the earlier report that mGluR5 knockout mice showed impaired contextual fear conditioning but normal fear conditioning in response to the CS (Lu et al, 1997). The disrupted LI in mGluR5 À/À mice mimics the pharmacologically disrupted LI in rats treated by mGluR5 antagonistFMPEP (Bills et al, 2005).…”

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

“…The cognitive impairment induced by MPEP is in agreement with the previous reports of mGlu5 receptor involvement in working and long-term memory, as measured by task performance in the eight-arm radial and Y-mazes (Lu et al, 1997;Balschun et al, 1999;Balschun and Wetzel, 2002;Manahan-Vaughan and Schuetz, 2002). In the Figure 7 Effects of combined lower doses of MPEP (3 mg/kg) and MK-801 (0.01 mg/kg) on the correct/total nosepokes ratio and total number of nosepokes in the instrumental learning task.…”

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

“…This has previously been reported by some groups (Bashir et al, 1993;Bortolotto et al, 1995;Richter-Levin et al, 1994;Riedel et al, 1995), and not by others (Chinestra et al, 1993;Manzoni et al, 1994;Selig et al, 1995). Also work from mGluR5 knockout mice have shown that NMDA-receptor mediated LTP is impaired in these animals (Jia et al, 1998;Lu et al, 1997). However the concentrations of these compound that was chosen allowed for a significantly robust LTP to remain.…”