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 poten tiation (LTP) appears to be controlled by a switch-like biochemical pr ocess 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 i nduction of LTP, perhaps because the experimental conditions used by s ome investigators inadvertently activate this 'molecular switch', ther eby 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-freque ncy stimulation. Moreover, stimulation protocols designed to deactivat e an inadvertently activated molecular switch had no effect on the ina bility of MCPG to block LTP. MCPG (through a switch-independent mechan ism) did inhibit the induction of LTP by a weak induction protocol. Ou r results thus suggest that MCPG-sensitive mGLURs are not required for the induction of LTP and that a mGLUR-activated 'molecular switch' do es not explain the inconsistent effects of MCPG on LTP. Instead, MCPG- sensitive mGLURs may have a modulatory role in the induction of LTP th at is most evident when LTP is induced by near threshold patterns of s ynaptic stimulation.