Aerial respiration in the fresh water mollusc Lymnaea stagnalis is controlled by an identified network of central pattern generating neurons (CPG). The CPG underlying central respiratory rhythmogenesis is comprised of three cells: namely RPeD1, VD4 and IP3I. IP3I and VD4 control expiration and inspiration, respectively, whereas RPeD1 initiates respiratory rhythmogenesis. Both in vivo and in vitro, RPeD1 stimulation is required to trigger respiratory episodes in IP3I and VD4; however, the intrinsic sources of this excitatory drive to RPeD1 in vivo, remain unknown. In this study, we demonstrate that the hypoxia-induced respiratory drive originates at the periphery and is conveyed to the CPG neurons via RPeD1. The peripheral chemoreceptor cells mediating this hypoxia sensitivity were subsequently identified and characterized and were found to resemble the mammalian carotid body chemoreceptors. Synapses between RPeD1 and the peripheral chemoreceptor cells (PCRC) were reconstructed in cell culture. We provide direct evidence that the efficacy of synaptic transmission between the PRCR and RPeD1 is highly modulated by both short- and long-term hypoxia and that this plasticity requires new gene transcription and de novo protein synthesis. Because both the peripheral (PCRC) and the central (CPC) components of respiratory rhythmogenesis in Lymnaea have features in common with mammals, the Lymnaea model thus provides us with an opportunity to elucidate mechanisms underlying neural control of breathing in a variety of animal species.