Differential expression of metabotropic glutamate and GABA receptors at neocortical glutamatergic and GABAergic axon terminals

Metabotropic glutamate (Glu) receptors (mGluRs) and GABA(B) receptors are highly expressed at presynaptic sites. To verify the possibility that the two classes of metabotropic receptors contribute to axon terminals heterogeneity, we studied the localization of mGluR1 alpha, mGluR5, mGluR2/3, mGluR7, and GABA(B1) in VGLUT1-, VGLUT2-, and VGAT- positive terminals in the cerebral cortex of adult rats. VGLUT1-positive puncta expressed mGluR1 alpha (similar to 5%), mGluR5 (similar to 6%), mGluR2/3 (similar to 22%), mGluR7 (similar to 17%), and GABA(B1) (similar to 40%); VGLUT2-positive terminals expressed mGluR1 alpha (similar to 10%), mGluR5 (similar to 11%), mGluR2/3 (similar to 20%), mGluR7 (similar to 28%), and GABA(B1) (similar to 25%); whereas VGAT-positive puncta expressed mGluR1 alpha (similar to 27%), mGluR5 (similar to 24%), mGluR2/3 (similar to 38%), mGluR7 (similar to 31%), and GABA(B1) (similar to 19%). Control experiments ruled out the possibility that postsynaptic mGluRs and GABA(B1) might have significantly biased our results. We also performed functional assays in synaptosomal preparations, and showed that all agonists modify Glu and GABA levels, which return to baseline upon exposure to antagonists. Overall, these findings indicate that mGluR1 alpha, mGluR5, mGluR2/3, mGluR7, and GABA(B1) expression differ significantly between glutamatergic and GABAergic axon terminals, and that the robust expression of heteroreceptors may contribute to the homeostatic regulation of the balance between excitation and inhibition.