Distinct receptors underlie glutamatergic signalling in inspiratory rhythm‐generating networks and motor output pathways in neonatal rat

Abstract

Despite the enormous diversity of glutamate (Glu) receptors and advances in understanding recombinant receptors, native Glu receptors underlying functionally identified inputs in active systems are poorly defined in comparison. In the present study we use UBP-302, which antagonizes GluR5 subunit-containing kainate (KA) receptors at ≤ 10 μM, but other KA and AMPA receptors at ≥ 100 μM, and rhythmically active in vitro preparations of neonatal rat to explore the contribution of non-NMDA receptor signalling in rhythm-generating and motor output compartments of the inspiratory network. At 10 μM, UBP-302 had no effect on inspiratory burst frequency or amplitude. At 100 μM, burst amplitude recorded from XII, C1 and C4 nerve roots was significantly reduced, but frequency was unaffected. The lack of a frequency effect was confirmed when local application of UBP-302 (100 μM) into the pre-Bötzinger complex (preBötC) did not affect frequency but substance P evoked a 2-fold increase. A UBP-302-sensitive (10 μM), ATPA-evoked frequency increase, however, established that preBötC networks are sensitive to GluR5 activation. Whole-cell recordings demonstrated that XII motoneurons also express functional GluR5-containing KA receptors that do not contribute to inspiratory drive, and confirmed the dose dependence of UBP-302 actions on KA and AMPA receptors. Our data provide the first evidence that the non-NMDA (most probably AMPA) receptors mediating glutamatergic transmission within preBötC inspiratory rhythm-generating networks are pharmacologically distinct from those transmitting drive to inspiratory motoneurons. This differential expression may ultimately be exploited pharmacologically to separately counteract depression of central respiratory rhythmogenesis or manipulate the drive to motoneurons controlling airway and pump musculature.

Studying respiratory rhythm generation in a developing bird: Hatching a new experimental model using the classic in vitro brainstem-spinal cord preparation

“…When SD episodes re-appeared near E8, rhythmogenesis is critically dependent on ionotropic glutamate receptors through the hatching period. The importance of glutamate is a consistent finding from rhythmic respiratory networks among many diverse taxa, including mammals (Ireland et al, 2008; Pace et al, 2007; Smith et al, 1991), turtles (Johnson and Mitchell, 1998), and frogs (Chen and Hedrick, 2008). …”

AMPA and metabotropic glutamate receptors cooperatively generate inspiratory‐like depolarization in mouse respiratory neuronsin vitro

“…Excitatory post‐synaptic potentials (EPSPs), largely mediated by AMPA receptors (Ge & Feldman, 1998; Shao et al. , 2003; Ireland et al. , 2008), depolarize the post‐synaptic membrane to open Ca 2+ channels.…”

The Cellular Building Blocks of Breathing

“…This multiplicity is critical for the generation of the large repertoire of behavioral functions that are served by this rhythm-generating network. A study by Ireland et al (231) has elegantly demonstrated that the type of non-NMDA-R (probably AMPA) that mediate glutamatergic synaptic transmission within the preBötC are different from the non-NMDA-R mediating the drive to motoneurons (231). …”