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Group II Metabotropic Glutamate Receptor (mGlu2 and mGlu3) Roles in Thalamic Processing

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
JournalBritish journal of pharmacology
DOIs
Published9 Aug 2021

Bibliographical note

Funding Information: This study is supported by a Biotechnology and Biological Sciences Research Council (BBSRC) grant (BB/H530570/1 to TES) and Eli Lilly and Company. Publisher Copyright: © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Documents

  • Final Accepted New Lilly Paper

    Final_Accepted_New_Lilly_Paper.pdf, 939 KB, application/pdf

    Uploaded date:09 Aug 2021

    Version:Accepted author manuscript

    Licence:CC BY

King's Authors

Abstract

Background and Purpose: As the thalamus underpins almost all aspects of behaviour, it is important to understand how the thalamus operates. Group II metabotropic glutamate (mGlu 2/mGlu 3) receptor activation reduces inhibition in thalamic nuclei originating from the surrounding thalamic reticular nucleus (TRN). Whilst an mGlu 2 component to this effect has been reported, in this study, we demonstrate that it is likely, largely mediated via mGlu 3. Experimental Approach: The somatosensory ventrobasal thalamus (VB) is an established model for probing fundamental principles of thalamic function. In vitro slices conserving VB–TRN circuitry from wild-type and mGlu 3 knockout mouse brains were used to record IPSPs and mIPSCs. In vivo extracellular recordings were made from VB neurons in anaesthetised rats. A range of selective pharmacological agents were used to probe Group II mGlu receptor function (agonist, LY354740; antagonist, LY341495; mGlu 2 positive allosteric modulator, LY487379 and mixed mGlu 2 agonist/mGlu 3 antagonist LY395756). Key Results: The in vitro and in vivo data are complementary and suggest that mGlu 3 receptor activation is largely responsible for potentiating responses to somatosensory stimulation by reducing inhibition from the TRN. Conclusions and Implications: mGlu 3 receptor activation in the VB likely enables important somatosensory information to be discerned from background activity. These mGlu 3 receptors are likely to be endogenously activated via ‘glutamate spillover’. In cognitive thalamic nuclei, this mechanism may be of importance in governing attentional processes. Positive allosteric modulation of endogenous mGlu 3 receptor activation may therefore enhance cognitive function in pathophysiological disease states, such as schizophrenia, thus representing a highly specific therapeutic target.

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