Metabotropic glutamate receptor, mGlu5, regulates hippocampal synaptic plasticity and is required for tetanisation-triggered changes in theta and gamma oscillations

•Enhancement of network oscillations after afferent stimulation predicts the longevity of LTP.•Theta, gamma and epsilon frequency ranges are particularly relevant.•Allosteric inhibition of mGlu5 suppresses oscillations that herald successful LTP.•Allosteric potentiation of mGlu5 enhances LTP and associated oscillations.•mGlu5, regulates hippocampal synaptic plasticity and associated changes in neuronal oscillations.

Hippocampal synaptic plasticity and learning are regulated by metabotropic glutamate receptors (mGlu) and particularly by mGlu5. In the hippocampus, synaptic plasticity is tightly linked to neuronal network oscillations in theta (5-10 Hz) and gamma (∼30-100 Hz) frequency ranges, and specific changes in theta and gamma spectral power can predict for the success of patterned afferent stimulation in inducing robust long-term potentiation (LTP). In this study, we hypothesized that activation of mGlu5 mediates tetanisation-driven changes in network oscillations and thereby determines the longevity of LTP. To explore this, we applied high-frequency stimulation (HFS) to the perforant path input to the dentate gyrus (DG), in the presence of the negative allosteric modulator, 2-methyl-6-(phenylethynyl)pyridine (MPEP), or the positive allosteric modulator (S)-(4-fluorophenyl)-[3-(3-(3-(4-fluorophenyl)-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl)]methanone (ADX47273). In freely behaving rats, administration of MPEP resulted in a significant impairment, whereas treatment with ADX47273 led to a significant enhancement, of LTP (>24 h) compared to vehicle-treated controls. Allosteric potentiation of mGlu5 also resulted in a significantly greater increase of the spectral power of theta and gamma oscillations within the period of 300 s after HFS, as compared to MPEP-treated animals or controls. Our findings show that the regulation of hippocampal LTP by mGlu5 is associated with modulation of network oscillatory activity in the period shortly after LTP induction. Taken together, these data demonstrate that changes in the spectral contents of local field activity that occur in response to patterned afferent stimulation require activation of mGlu5 and may be instrumental for the successful expression of persistent LTP.This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.