Regulation by Metabotropic Glutamate Receptor 5 of LTP in the Dentate Gyrus of Freely Moving Rats: Relevance for Learning and Memory Formation

Group I metabotropic glutamate (mGlu) receptors play a critical role in the regulation of hippocampal long-term potentiation (LTP) in vivo. Little is known, however, about the contribution of the individual subtypes mGlu1 and mGlu5 to learning processes and LTP. We investigated the involvement of mGlu5 in hippocampal LTP and spatial learning using the selective antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). Rats were chronically implanted with recording and stimulating electrodes to enable measurement of evoked potentials from the medial perforant path - dentate gyrus granule cell synapses. An injection cannula was inserted into the ipsilateral cerebral ventricle to enable drug application. Experiments were begun 10 days subsequent to the implantation procedure. Robust LTP which lasted for over 25 h was generated using 200 Hz tetanization. MPEP, applied in concentrations which did not affect basal synaptic transmission, dose-dependently impaired the induction and expression of LTP. Application of MPEP 5 min after tetanization inhibited late LTP (>24 h). The effects of daily MPEP application on performance in an eight-arm radial maze were evaluated. MPEP-treated rats showed deficits in reference and working memory performance compared to vehicle-treated controls. Rearing, grooming and locomotor activity were unaffected in MPEP-treated animals. These data highlight the importance of mGlu5 for both LTP and spatial learning and emphasize the significance of these receptors for information storage on both synaptic and behavioural levels.