Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum

Abstract

The striatum plays critical roles in action control and cognition, and activity of striatal neurons is driven by glutamatergic input. Inhibition of glutamatergic inputs to projection neurons and interneurons of the striatum by presynaptic G protein-coupled receptors (GPCRs) stands to modulate striatal output and striatum-dependent behaviors. Despite knowledge that a substantial number of glutamatergic inputs to striatal neurons originate in the thalamus, most electrophysiological studies assessing GPCR modulation do not differentiate between effects on corticostriatal and thalamostriatal transmission, and synaptic inhibition is frequently assumed to be mediated by activation of GPCRs on corticostriatal terminals. We used optogenetic techniques and recently-discovered pharmacological tools to dissect the effects of a prominent presynaptic GPCR, metabotropic glutamate receptor 2 (mGlu2), on corticostriatal vs. thalamostriatal transmission. We found that an agonist of mGlu2 and mGlu3 induces long-term depression (LTD) at synapses onto MSNs from both the cortex and the thalamus. Thalamostriatal LTD is selectively blocked by an mGlu2-selective negative allosteric modulator and reversed by application of an antagonist following LTD induction. Activation of mGlu2/3 also induces LTD of thalamostriatal transmission in striatal cholinergic interneurons (CINs), and pharmacological activation of mGlu2/3 or selective activation of mGlu2 inhibits CIN-mediated dopamine release evoked by selective stimulation of thalamostriatal inputs. Thus, mGlu2 activation exerts effects on striatal physiology that extend beyond modulation of corticostriatal synapses, and has the potential to influence cognition and striatum-related disorders via inhibition of thalamus-derived glutamate and dopamine release.

Serotonergic Signaling Controls Input-Specific Synaptic Plasticity at Striatal Circuits

“…Our findings add to the limited knowledge of the intracellular signaling pathways regulating the thalamostriatal system, in particular the molecular mechanisms underlying synaptic depression of thalamo-dSPN synapses (Atwood et al, 2014;Ellender et al, 2011;Johnson et al, 2017;Parker et al, 2016;Wu et al, 2015). t-LTD at thalamostriatal inputs has been shown to be independent of eCBs released from the postsynaptic SPN (Wu et al, 2015).…”

“…In this experimental setting, the STDP protocol failed to induce significant changes in o-EPSP Ctx (98% ± 8% of baseline, n = 7, p > 0.05; Figure 4C), even when applied in the presence of RS39604 (5 mM; 92% ± 6% of baseline, n = 8, p > 0.05; Figure 4C). To corroborate this lack of involvement of corticostriatal synapses in a second model, we injected an adeno-associated viral (AAV) vector encoding ChR2-eYFP under the control of the CaMKIIa promoter [rAAV5-CaMKIIa-ChR2(H134R)-eYFP] into the M1 motor cortex region of C57BL/6J mice (Johnson et al, 2017) ( Figure S6A). As with Thy1-ChR2 mice ( Figure 4C), the STDP protocols failed to induce significant changes in dSPNs o-EPSP Ctx , regardless of the presence or absence of RS39604 (dSPN Ctx , 97% ± 6% of baseline, n = 7, p > 0.05; dSPN Ctx + RS39604, 90% ± 2% of baseline, n = 6, p > 0.05; dSPN Ctx versus dSPN Ctx + RS39604, p = 0.7 Mann Whitney test; Figures S6B and S6C).…”

“…These results also suggest that gating of t-LTD due to decreased 5-HT signaling is in fact occurring at thalamostriatal inputs. To test this, we virally expressed ChR2 in the thalamus of C57BL/6J mice ( Figure 4D) (Ellender et al, 2013;Johnson et al, 2017) and measured light-evoked EPSPs (o-EPSP Thal ) at thalamostriatal connections. To induce plasticity, we applied the same post-pre STDP paradigm described for corticostriatal synapses ( Figure 4B).…”

Dopamine neuron glutamate cotransmission evokes a delayed excitation in lateral dorsal striatal cholinergic interneurons

“…In contrast, slow EPSCs in ldStr ChIs are reliably evoked with single spikes, at low frequency, suggesting that mGluR1 receptors are closer to synaptic release sites in ChIs than in Purkinje cells or DA neurons. ChIs, as well as SPNs, express both mGluR1 and iGluRs, and iGluR responses are evoked in SPNs by stimulation of other glutamate inputs ( Ding et al, 2010 ; Johnson et al, 2017 ), but not mGluR1 responses. Furthermore, mGluR1 is not enriched in ChIs.…”

Bioequivalence and Bioavailability of Receptors Dopamine (D2) and Serotonin in the Action of Antipsychotic Drugs

“…Doses of Amisulpride between 600-900 mg/day give occupancy rate D2 of 70-80%, while the doses >1100 mg/ day give occupancy rate D2 of >85%, and at these higher doses may be observed EPS. Blocking the receptors 5HT2A and preferential blocking certain subtypes of dopamine receptors it was an assumption relevant in defining the mechanism effectiveness atypical or second generation antipsychotics in the treatment of negative symptoms [7]. The studies PET of atypical antipsychotics showed an extended of the receptors occupancy rate 5HT2A in the cerebral cortex clozapine, olanzapine, risperidone and quetiapine, but not amisulpride.…”