Switch from Facilitation to Inhibition of Excitatory Synaptic Transmission by Group I mGluR Desensitization

We have explored whether the desensitization of metabotropic glutamate receptors (mGluRs) coupled to phosphoinositide hydrolysis affects the role that they play in modulating glutamate release. In hippocampal nerve terminals, the agonist 3,5-dihydroxyphenylglycine (DHPG) facilitated evoked glutamate release, but a second stimulation 5 min later reduced rather than facilitated release. After a 30 min interval between stimulations, DHPG again facilitated glutamate release. In hippocampal slices, DHPG caused an inhibition of excitatory postsynaptic currents (EPSCs) recorded from CA1 neurons. However, when the effects of ambient glutamate were prevented, mGluR activation initially induced a facilitation of synaptic transmission, followed by an inhibition. We conclude that group I mGluRs have a dual action on glutamate release, switching from facilitatory to inhibitory upon receptor desensitization triggered by low concentrations of glutamate.