title: Differential effect of the mGlu5 receptor positive allosteric modulator ADX-47273 on early and late hippocampal LTP.
abstract: Conflicting findings are reported in the literature about the involvement of the mGlu5 receptor in hippocampal long-term potentiation (LTP), which might be a consequence of different sub-types of LTP induced by the investigators due to the specific experimental conditions used. A comparable controversy came up in the past concerning the influence of different experimental conditions on the involvement of L-type voltage dependent calcium channels (L-VDCCs) and NMDA receptors in hippocampal LTP. In this study, two stimulation protocols with otherwise identical conditions were used to probe modulatory effects of mGlu5 receptor activation in NMDA receptor and L-VDCCs dependent CA1 LTP: weak high frequency stimulation (20 stimuli at 100 Hz) to induce early LTP and repeated strong high frequency stimulation (3 times 100 stimuli at 100 Hz with 5 min interval) to induce late LTP, which - in contrast to early LTP - was shown to be protein-synthesis dependent. Using the NMDA receptor antagonist MK-801 and the L-type calcium channel blocker nifedipine, early LTP was shown to be dependent on NMDA receptors only, whereas late LTP was demonstrated to be dependent on NMDA receptors and L-VDCCs in about equal parts. Moreover, late LTP, but not early LTP, was increased by the mGlu5 receptor positive allosteric modulator ADX-47273, indicating that artificial augmentation of mGlu5 receptor activation by endogenous glutamate may boost the protein-synthesis dependent form of LTP but not the protein-synthesis independent form.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Department of CNS Diseases Research, Biberach, Germany. Katja.Kroker@boehringer-ingelheim.com
authors.forename: Katja S
authors.initials: KS
authors.lastname: Kroker
authors.forename: Georg
authors.initials: G
authors.lastname: Rast
authors.forename: Holger
authors.initials: H
authors.lastname: Rosenbrock
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis / Q000502:physiology*; D013997:Time Factors
chemical_list: D010069:Oxadiazoles; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C533862:S-(4-fluorophenyl)-(3-(3-(4-fluorophenyl)-(1,2,4)-oxadiazol-5-yl)piperidin-1-yl)methanone