title: Activation of Metabotropic Glutamate Receptor 7 Is Required for Induction of Long-Term Potentiation at SC-CA1 Synapses in the Hippocampus.
abstract: Of the eight metabotropic glutamate (mGlu) receptor subtypes, only mGlu7 is expressed presynaptically at the Schaffer collateral (SC)-CA1 synapse in the hippocampus in adult animals. Coupled with the inhibitory effects of Group III mGlu receptor agonists on transmission at this synapse, mGlu7 is thought to be the predominant autoreceptor responsible for regulating glutamate release at SC terminals. However, the lack of mGlu7-selective pharmacological tools has hampered direct testing of this hypothesis. We used a novel, selective mGlu7-negative allosteric modulator (NAM), ADX71743, and a newly described Group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu7 in modulating transmission in hippocampal area CA1 in adult C57BL/6J male mice. Interestingly, although mGlu7 agonists inhibit SC-CA1 EPSPs, we found no evidence for activation of mGlu7 by stimulation of SC-CA1 afferents. However, LSP4-2022 also reduced evoked monosynaptic IPSCs in CA1 pyramidal cells and, in contrast to its effect on SC-CA1 EPSPs, ADX71743 reversed the ability of high-frequency stimulation of SC afferents to reduce IPSC amplitudes. Furthermore, blockade of mGlu7 prevented induction of LTP at the SC-CA1 synapse and activation of mGlu7 potentiated submaximal LTP. Together, these data suggest that mGlu7 serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu7 by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu7-mediated disinhibition is required for induction of LTP at the SC-CA1 synapse, suggesting that mGlu7 could serve as a novel therapeutic target for treatment of cognitive disorders.
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery.
authors.forename: Rebecca
authors.identifier: http://orcid.org/0000-0001-5650-1187
authors.initials: R
authors.lastname: Klar
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Walker
authors.affiliation: Department of Anesthesiology.
authors.forename: Dipanwita
authors.initials: D
authors.lastname: Ghose
authors.affiliation: Department of Anesthesiology, Department of Molecular Physiology and Biophysics, and Department of Psychiatry, Vanderbilt University Medical Center, Nashville, Tennessee 37232, and.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Grueter
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232.
authors.forename: Corey R
authors.identifier: http://orcid.org/0000-0001-9194-4784
authors.initials: CR
authors.lastname: Hopkins
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery.
authors.forename: Zixiu
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Jeff.Conn@vanderbilt.edu Colleen.Niswender@vanderbilt.edu.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Jeff.Conn@vanderbilt.edu Colleen.Niswender@vanderbilt.edu.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000075402:Channelrhodopsins; D004558:Electric Stimulation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D007395:Interneurons / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010320:Parvalbumins / Q000235:genetics; D018408:Patch-Clamp Techniques; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: D000075402:Channelrhodopsins; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D010320:Parvalbumins; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7
keywords: LTP; glutamate; hippocampus; mGlu; mGlu7; mGlur7