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

Metabotropic glutamate receptors (mGluRs) modulate neuronal function by aff ecting 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 reducti on of inspiratory-modulated synaptic currents and an increase of neuronal e xcitability. We hypothesized that these actions were mediated by different mGluR subtypes. We have now identified the involvement of mGluR subtypes an d their roles in modulating the excitability of PMNs and the consequent ins piratory motor output in an in vitro neonatal rat brainstem-spinal cord pre paration. Activation of postsynaptic group-I mGluRs increases PMN excitabil ity, associated with the production of an inward current and a decrease in membrane conductance, whereas activation of group-II or group-III mGluRs de creases PMN inspiratory-modulated synaptic current, probably via a presynap tic mechanism. To confirm further the distinction and the involvement of gr oup-I and group-II/-III receptor subtypes affecting PMN excitability, we us ed the membrane permeable cAMP analog 8-bromo-cAMP (8-Br-cAMP) to elevate i ntracellular cAMP concentration to mask or occlude any effects mediated via the cAMP cascade. 8-Br-cAMP attenuated the reduction of the inspiratory-mo dulated activity of PMNs by both (S)-4-carboxy-3-hydroxyphenylglycine (4C3H PG) and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4), agonists for group-I I 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 phas e. We conclude that three groups of mGluRs are functionally expressed in th e 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.