Transporter-dependent regulation of glycine neurotransmission in the respiratory network: the role of GlyT1 (SLC6A9) GlyT2 (SLC6A5) and Asc-1 (SLC7A10)

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Breathing is controlled by a neuronal network in the medulla and pons. Although the principal rhythm generator was shown to be glutamatergic, glycine-dependent neurotransmission exerts important modulatory functions and is critical for the coordinated activity of the respiratory network. The regulation of the extracellular glycine concentration is achieved by high affinity large capacity glycine transporters that mediate the transport of glycine across the membranes of presynaptic terminal or glial cells surrounding the synapse. Although most cells at glycine-dependent synapses express more than one transporter with high affinity for glycine, their functional interaction is only poorly understood. In this project, we now plan to investigated, how high affinity transporters for glycine, i.e. the predominantly astroglial expressed glycine transporter 1 (GlyT1; Slc6A9) and alanine-serine-cysteine-1 transporter (Asc-1; Slc7A10) and the neuronal expressed GlyT2 (Slc6a5) interact to regulate synapse homeostasis and how their contributions change during development. Thereby, we will not only foster our understand on the transporter functions per se, but will also extend our knowledge how glycine-dependent neurotransmission is involved in the regulation of the respiratory activity. In addition, it might provide novel insights on the mechanism how certain drugs like general anesthetics exert respiratory depressive effects. We are planning to tackle this topic by an interdisciplinary approach using genetically-modified mouse lines together with virus-based techniques and RNAi methods to manipulate the cellular expression of the different transporters. This will be combined with biochemical and physiological methods to allow the analysis of the respiratory activity in mice in-situ as well as in-vivo. Taken together this will help us to delineate the precise roles of the respective transporters at inhibitory synapses and describe in detail how these transporters interact functionally. This will include the description of the impact of respective transporters on glycine turnover at inhibitory glycinergic synapses. Thereby this project will enhance our understanding how transporter function correlates with alteration in synaptic transmission in respiratory neurons and with the breathing behavior.