The regulation of hippocampal LTP by the molecular switch, a form of metaplasticity, requires mGlu5 receptors.

Abstract The role of metabotropic glutamate (mGlu) receptors in long-term potentiation (LTP) in the hippocampus is controversial. In the present study, we have used mice in which the mGlu 1 , mGlu 5 or mGlu 7 receptor has been deleted, by homologous recombination, to study the role of these receptor subtypes in LTP at CA1 synapses. We investigated the effects of the knockouts on both LTP and the molecular switch, a form of metaplasticity that renders LTP insensitive to the actions of the mGlu receptor antagonist MCPG (( S )-α-methyl-4-carboxyphenylglycine). We find that LTP is readily induced in the three knockouts and in an mGlu 1 and mGlu 5 double knockout. In addition, the molecular switch operates normally in either the mGlu 1 or mGlu 7 knockout. In contrast, the molecular switch is completely non-functional in the mGlu 5 knockout, such that MCPG invariably blocks the induction of additional LTP in an input where LTP has already been induced. The effect of the mGlu 5 receptor knockout was replicated in wildtype mouse slices perfused with the specific mGlu 5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)-pyridine). In addition, the mGlu 5 selective agonist CHPG (( RS )-2-chloro-5-hydroxyphenylglycine) sets the molecular switch. These data demonstrate that the operation of the molecular switch requires activation of mGlu 5 receptors.