King's College London

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.