Neurotransmitter transporters expressed in glial cells as regulators of synapse function

Abstract

Synaptic neurotransmission at high temporal and spatial resolutions requires efficient removal and/or inactivation of presynaptically released transmitter to prevent spatial spreading of transmitter by diffusion and allow for fast termination of the postsynaptic response. This action must be carefully regulated to result in the fine tuning of inhibitory and excitatory neurotransmission, necessary for the proper processing of information in the central nervous system. At many synapses, high-affinity neurotransmitter transporters are responsible for transmitter deactivation by removing it from the synaptic cleft. The most prevailing neurotransmitters, glutamate, which mediates excitatory neurotransmission, as well as GABA and glycine, which act as inhibitory neurotransmitters, use these uptake systems. Neurotransmitter transporters have been found in both neuronal and glial cells, thus suggesting high cooperativity between these cell types in the control of extracellular transmitter concentrations. The generation and analysis of animals carrying targeted disruptions of transporter genes together with the use of selective inhibitors have allowed examining the contribution of individual transporter subtypes to synaptic transmission. This revealed the predominant role of glial expressed transporters in maintaining low extrasynaptic neurotransmitter levels. Additionally, transport activity has been shown to be actively regulated on both transcriptional and post-translational levels, which has important implications for synapse function under physiological and pathophysiological conditions. The analysis of these mechanisms will enhance not only our understanding of synapse function but will reveal new therapeutic strategies for the treatment of human neurological diseases.