Multiple Actions of 1S,3R-ACPD in Modulating Endogenous Synaptic Transmission to Spinal Respiratory Motoneurons

Abstract

To determine physiological roles of metabotropic glutamate receptors (mGluRs) affecting breathing, we examined the effects of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) on synaptic transmission and excitability of phrenic motoneurons (PMNs) in an in vitro neonatal rat brainstem/spinal cord preparation. The effects of 1S,3R-ACPD were multiple, including reduction of inspiratory-modulated synaptic currents and increase of neuronal excitability via an inward current (I acpd ) associated with a decrease of membrane conductance. The mechanism underlying synaptic depression was examined. We found that 1S,3R-ACPD reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents. The current induced by exogenous AMPA was not significantly affected by 1S,3R-ACPD. These results suggest that 1S,3R-ACPD-induced reduction of inspiratory synaptic currents is mediated by presynaptic mGluRs. We also examined the ionic basis for I acpd . We found that I acpd had a reversal potential of approximately Ϫ100 mV, close to the estimated E K ϩ (Ϫ95 mV). Elevating extracellular [K ϩ ] to 9 mM reduced the I acpd reversal potential to Ϫ75 mV. The K ϩ channel blocker Ba 2ϩ induced an inward current with a reversal potential at Ϫ93 mV associated with a decrease of membrane conductance, closely resembling the effect of 1S,3R-ACPD. Moreover, Ba 2ϩ occluded 1S,3R-ACPD effects. In the presence of Ba 2ϩ , I acpd and the 1S,3R-ACPD-induced decrease of membrane conductance were diminished. Our data indicate that the dominant component of I acpd results from the blockade of a Ba 2ϩ -sensitive resting K ϩ conductance. We conclude that the activation of mGluRs affects the inspiratory-modulated activity of PMNs via distinct mechanisms at pre-and postsynaptic sites.

Synaptic Control of Motoneuronal Excitability

“…Both group II and group III mGluR reduce spinal segmental transmission to lumbar motoneurons (181, 541,562,618,1243) and bulbospinal inspiratory synaptic inputs to phrenic motoneurons (301,302). Only synaptic events are depressed.…”

“…These two groups of mGluR have no effect on postsynaptic depolarization induced by exogenous EAA (302,541) or postsynaptic membrane intrinsic properties (181, 301). Moreover, the frequency of mEPSC is significantly reduced by both group II and group III agonists, whereas the mEPSC amplitude is unaffected (301,302). This suggests that activation of presynaptic group II and group III mGluR inhibits glutamate release to motoneurons.…”

“…Another possible mechanism is the direct modulation of the exocytotic machinery by influencing the availability of vesicles or their probability of release (468). The activation of mGluR is effective in reducing the frequency of spontaneous mEPSC when presynaptic action potentials are blocked in motoneurons (301,302) and in other neurons, such as in hippocampus (419,779,1091) and striatum (1282). These spontaneous mEPSC seem independent of presynaptic Ca 2+ influx since they persist in the presence of Ca 2+ channel blockers (419,1090,1091,1102).…”

“…Modulation of intrinsic membrane properties-Activation of mGluR, most likely of group I, causes membrane depolarization (287,301,302,316,540,560,561,1242,1244). This effect persists after block of synaptic transmission, suggesting mediation by postsynaptic receptors.…”

“…In rat phrenic (301,302) and trigeminal (287) motoneurons, depolarization is due to an inward current produced by activation of postsynaptic group I mGluR (301). This inward current consists of at least two components: a dominant component resulting from the blockade of a Ba 2+ -sensitive resting K + current (287,302) and an unidentified Ba 2+ -resistant component (302). Inhibition of this tonic K + current results in membrane depolarization and increase in membrane resistance, both effects increasing motoneuronal excitability.…”