An analysis of the stimulus requirements for setting the molecular switch reveals a lower threshold for metaplasticity than synaptic plasticity

The requirements for the synaptic activation of metabotropic glutamate (mGlu) receptors and for the induction of metaplasticity in the hippocampus are not known. In the present study, we have investigated the synaptic activation of mGlu5 receptors and the setting of the molecular switch, a form of metaplasticity, at CA1 synapses in the mouse hippocampus. We find that as few as eight stimuli (delivered at 100 Hz) are sufficient to set the molecular switch, since a subsequent tetanus delivered to the same input is able to induce long-term potentiation (LTP) in the presence of the mGlu receptor antagonist MCPG ((S)-α-methyl-4-carboxyphenylglycine). In addition, we find that the molecular switch can be activated over a wide frequency range. When 10 shocks were delivered the threshold frequency was 4 Hz. The ability of 10 shocks (delivered at 100 Hz) to set the molecular switch was lost in the mGlu5 knockout. These data show that mGlu5 receptors can be activated synaptically and metaplasticity can be induced by relatively few stimuli. Indeed, metaplasticity was induced by stimuli that were subthreshold for the induction of LTP per se. Thus, metaplasticity has a lower threshold than the synaptic plasticity that it regulates.