AUTHOR=Vergassola Matteo , Olivero Guendalina , Cisani Francesca , Usai Cesare , Bossi Simone , Puliti Aldamaria , Pittaluga Anna 

TITLE=Presynaptic mGlu1 Receptors Control GABAB Receptors in an Antagonist-Like Manner in Mouse Cortical GABAergic and Glutamatergic Nerve Endings

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=11

YEAR=2018

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2018.00324

DOI=10.3389/fnmol.2018.00324

ISSN=1662-5099

ABSTRACT=<p>Mouse cortical GABAergic synaptosomes possess presynaptic inhibitory GABA<sub>B</sub> autoreceptors. Accordingly, (±)baclofen (3 μM) inhibits in a CGP53423-sensitive manner the 12 mM KCl-evoked release of preloaded [<sup>3</sup>H]GABA. Differently, the existence of presynaptic release-regulating metabotropic glutamate type 1 (mGlu1) heteroreceptors in these terminals is still matter of discussion, although confocal microscopy unveiled the existence of mGlu1α with GABA<sub>B1</sub> or GABA<sub>B2</sub> proteins in cortical VGAT-positive synaptosomes. The group I mGlu agonist 3,5-DHPG failed to modify on its own the 12 mM KCl-evoked [<sup>3</sup>H]GABA exocytosis from cortical nerve endings, but, when added concomitantly to the GABA<sub>B</sub> agonist, it significantly reduced the 3 μM (±)baclofen-induced inhibition of [<sup>3</sup>H]GABA exocytosis. Conversely, the mGlu1 antagonist LY367385 (0.03–1 μM), inactive on its own on GABA exocytosis, amplified the 3 μM (±)baclofen-induced inhibition of [<sup>3</sup>H]GABA overflow. The ( ± )baclofen-induced inhibition of [<sup>3</sup>H]GABA exocytosis was more pronounced in cortical synaptosomes from <italic>Grm1<sup>crv4/crv4</sup></italic> mice, which bear a spontaneous mutation of the <italic>Grm1</italic> gene leading to the functional inactivation of the mGlu1 receptor. Inasmuch, the expression of GABA<sub>B2</sub> receptor protein in cortical synaptosomal lysates from <italic>Grm1<sup>crv4/crv4</sup></italic> mice was increased when compared to controls. Altogether, these observations seem best interpreted by assuming that mGlu1 coexist with GABA<sub>B</sub> receptors in GABAergic cortical synaptosomes, where they control GABA receptors in an antagonist-like manner. We then asked whether the mGlu1-mediated control of GABA<sub>B</sub> receptors is restricted to GABAergic terminals, or if it occurs also in other subpopulations of nerve endings. Release-regulating GABA<sub>B</sub> receptors also exist in glutamatergic nerve endings. (±)baclofen (1 μM) diminished the 12 mM KCl-evoked [<sup>3</sup>H]<sc>D</sc>-aspartate overflow. Also in these terminals, the concomitant presence of 1 μM LY367385, inactive on its own, significantly amplified the inhibitory effect exerted by (±)baclofen on [<sup>3</sup>H]<sc>D</sc>-aspartate exocytosis. Confocal microscopy confirmed the colocalization of mGlu1 with GABA<sub>B1</sub> and GABA<sub>B2</sub> labeling in vesicular glutamate type1 transporter-positive particles. Our results support the conclusion that mGlu1 receptors modulate in an antagonist-like manner presynaptic release-regulating GABA<sub>B</sub> receptors. This receptor–receptor interaction could be neuroprotective in central disease typified by hyperglutamatergicity.</p>