The molecular switch hypothesis fails to explain the inconsistent effects of the metabotropic glutamate receptor antagonist MCPG on long-term potentiation.

In the CA1 region of the hippocampus, the induction of long-term potentiation (LTP) appears to be controlled by a switch-like biochemical process that is persistently activated following metabotropic glutamate receptor (mGLUR) activation. However, the mGLUR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) does not consistently block the induction of LTP, perhaps because the experimental conditions used by some investigators inadvertently activate this 'molecular switch', thereby fulfilling the requirement for mGLUR activation and rendering LTP insensitive to the effects of mGLUR antagonists. In mouse hippocampal slices we observed that MCPG does not block LTP induced by high-frequency stimulation, Moreover, stimulation protocols designed to deactivate an inadvertently activated molecular switch had no effect on the inability of MCPG to block LTP. MCPG (through a switch-independent mechanism) did inhibit the induction of LTP by a weak induction protocol. Our results thus suggest that MCPT-sensitive mGLURs are not required for the induction of LTP and that a mLGUR-activated 'molecular switch' does not explain the inconsistent effects of MCPG on LTP. Instead, MCPG-sensitive mGLURs may have a modulatory role in the induction of LTP that is most evident when LTP is induced by near threshold patterns of synaptic stimulation.