Heterogeneous distribution and utilization of inhibitory neurotransmitter transporters

Abstract

Neurotransmitter homeostasis is important for proper synaptic signal transmission. Synaptically released neurotransmitters are recycled by direct reuptake into the presynaptic terminal and/or uptake into perisynaptic astrocyte processes. In the latter case, most neurotransmitters are metabolized and shuttled back to the presynaptic terminal to restore the neurotransmitter content in that compartment. In various regions of the central nervous system (CNS), the neurotransmitters glycine and GABA are heterogeneously utilized for inhibition of neuronal activity – glycine predominantly in caudal regions, GABA predominantly in rostral ones. Accordingly, respective transporters are used in neurons and astrocytes. Both cell types utilize different members of the neurotransmitter transporter family in a region-dependent manner. While glycine transporter (GlyT) 1 is predominantly utilized in astrocytes, GlyT2 is prevailing in neurons. The GABA transporters (GAT)‑1 and ‑3 are not distinctly attributed to neurons or astrocytes, and transporter localization depends on the CNS region. Additionally, there is a complex interplay of different neurotransmitters and respective transporters as the uptake of one neurotransmitter into neurons as well as astrocytes can trigger the release of other transmitters from both cell types. This review summarizes the heterogeneous distribution and utilization of the four inhibitory neurotransmitter transporters GlyT1, GlyT2, GAT‑1, and GAT‑3 in olfactory bulb, retina, cortex, hippocampus, cerebellum, brainstem, thalamus, and spinal cord. Furthermore, it elaborates possible functional consequences of the transporter interplay for neurotransmitter homeostasis.