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      mGlu 5 Positive Allosteric Modulators Facilitate Long-Term Potentiation via Disinhibition Mediated by mGlu 5-Endocannabinoid Signaling

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          Abstract

          Metabotropic glutamate (mGlu) receptor type 5 (mGlu 5) positive allosteric modulators (PAMs) enhance hippocampal long-term potentiation (LTP) and have cognition-enhancing effects in animal models. These effects were initially thought to be mediated by potentiation of mGlu 5 modulation of N-methyl- d-aspartate receptor (NMDAR) currents. However, a biased mGlu 5 PAM that potentiates Gα q-dependent mGlu 5 signaling, but not mGlu 5 modulation of NMDAR currents, retains cognition-enhancing effects in animal models, suggesting that potentiation of NMDAR currents is not required for these in vivo effects of mGlu 5 PAMs. However, it is not clear whether the potentiation of NMDAR currents is critical for the ability of mGlu 5 PAMs to enhance hippocampal LTP. We now report the characterization of effects of two structurally distinct mGlu 5 PAMs, VU-29 and VU0092273, on NMDAR currents and hippocampal LTP. As with other mGlu 5 PAMs that do not display observable bias for potentiation of NMDAR currents, VU0092273 enhanced both mGlu 5 modulation of NMDAR currents and induction of LTP at the hippocampal Schaffer collateral (SC)-CA1 synapse. In contrast, VU-29 did not potentiate mGlu 5 modulation of NMDAR currents but induced robust potentiation of hippocampal LTP. Interestingly, both VU-29 and VU0092273 suppressed evoked inhibitory postsynaptic currents (eIPSCs) in CA1 pyramidal cells, and this effect was blocked by the cannabinoid receptor type 1 (CB1) antagonist AM251. Furthermore, AM251 blocked the ability of both mGlu 5 PAMs to enhance LTP. Finally, both PAMs failed to enhance LTP in mice with the restricted genetic deletion of mGlu 5 in CA1 pyramidal cells. Taken together with previous findings, these results suggest that enhancement of LTP by mGlu 5 PAMs does not depend on mGlu 5 modulation of NMDAR currents but is mediated by a previously established mechanism in which mGlu 5 in CA1 pyramidal cells induces endocannabinoid release and CB1-dependent disinhibition.

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          The orphan receptor GPR55 is a novel cannabinoid receptor.

          The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes. Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPgammaS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the G-protein coupling was determined and further demonstrated by measuring activity of downstream signalling pathways. We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GTPgammaS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1 or CB2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Galpha13 and can mediate activation of rhoA, cdc42 and rac1. These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB1 and CB2 described here will permit delineation of its physiological function(s).
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            Interneuron cell types are fit to function.

            Understanding brain circuits begins with an appreciation of their component parts - the cells. Although GABAergic interneurons are a minority population within the brain, they are crucial for the control of inhibition. Determining the diversity of these interneurons has been a central goal of neurobiologists, but this amazing cell type has so far defied a generalized classification system. Interneuron complexity within the telencephalon could be simplified by viewing them as elaborations of a much more finite group of developmentally specified cardinal classes that become further specialized as they mature. Our perspective emphasizes that the ultimate goal is to dispense with classification criteria and directly define interneuron types by function.
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              Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5.

              Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation. We now report that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning, which is not. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis that LTP is involved in some, but not all, forms of learning.
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                Author and article information

                Journal
                ACS Pharmacol Transl Sci
                ACS Pharmacol Transl Sci
                pt
                aptsfn
                ACS Pharmacology & Translational Science
                American Chemical Society
                2575-9108
                15 May 2019
                14 June 2019
                : 2
                : 3
                : 198-209
                Affiliations
                [1] Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, §Department of Chemistry, Vanderbilt Kennedy Center, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States
                Author notes
                Article
                10.1021/acsptsci.9b00017
                6591772
                31259318
                d0e4a38f-fe9e-4b6d-b2bc-c6ddea51b5c4
                Copyright © 2019 American Chemical Society

                This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

                History
                : 26 February 2019
                Categories
                Article
                Custom metadata
                pt9b00017
                pt-2019-00017z

                positive allosteric modulators,mglu5,hippocampus,long-term potentiation,endocannabinoid

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