Distinct subtypes of metabotropic glutamate receptors mediate differential actions on excitability of spinal respiratory motoneurons

Metabotropic glutamate receptors (mGluRs) modulate neuronal function by affecting excitability and altering synaptic transmission. We have shown that the mGluR agonist (1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD) has multiple actions on phrenic motoneurons (PMNs), including reduction of inspiratory-modulated synaptic currents and an increase of neuronal excitability. We hypothesized that these actions were mediated by different mGluR subtypes. We have now identified the involvement of mGluR subtypes and their roles in modulating the excitability of PMNs and the consequent inspiratory motor output in an in vitro neonatal rat brainstem-spinal cord preparation. Activation of postsynaptic group-I mGluRs increases PMN excitability, associated with the production of an inward current and a decrease in membrane conductance, whereas activation of group-II or group-III mGluRs decreases PMN inspiratory-modulated synaptic current, probably via a presynaptic mechanism. To confirm further the distinction and the involvement of group-I and group-II/-III receptor subtypes affecting PMN excitability, we used the membrane permeable cAMP analog 8-bromo-cAMP (8-Br-cAMP) to elevate intracellular cAMP concentration to mask or occlude any effects mediated via the cAMP cascade. 8-Br-cAMP attenuated the reduction of the inspiratory-modulated activity of PMNs by both (S)-4-carboxy-3-hydroxyphenylglycine (4C3HPG) and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4), agonists for group-II and group-III mGluRs, respectively, but did not affect the actions of 3,5-dihydroxyphenylglycine (DHPG), an agonist for group-I mGluRs. These three groups of mGluRs are all endogenously activated during the inspiratory phase. We conclude that three groups of mGluRs are functionally expressed in the phrenic nucleus and that their activation modulates PMN excitability via distinct mechanisms, with group-I acting at postsynaptic sites and group-II and group-III acting at presynaptic sites.