Abstract
Glutamate uptake is a process mediated by sodium-dependent glutamate transporters, preventing glutamate spillover from the synapse. Typically, astrocytes express higher amounts of glutamate transporters, thus being responsible for most of the glutamate uptake; nevertheless, neurons can also express these transporters, albeit in smaller concentrations. When not regulated, glutamate uptake can lead to neuronal death. Indeed, the majority of the studies regarding glutamate transporters have focused on excitotoxicity and the subsequent neuronal loss. However, later studies have found that glutamate uptake is not a static process, evincing a possible correlation between this phenomenon and the efficiency of synaptic transmission and plasticity. In this review, we will focus on the role of the increase in glutamate uptake that occurs during long-term potentiation (LTP) in the hippocampus, as well as on the impairment of long-term depression (LTD) under the same conditions. The mechanism underpinning the modulatory effect of glutamate transporters over synaptic plasticity still remains unascertained; yet, it appears to have a more prominent effect over the N-methyl-D-aspartate receptor (NMDAR), despite changes in other glutamate receptors may also occur.
Highlights
Glutamate was first classified as a neurotransmitter in the 1950s (Hayashi, 1952), and is presently acknowledged as the major excitatory neurotransmitter in the mammalian brain
Within the Central Nervous System (CNS), glutamate acts by binding to receptors coupled to ionotropic channels, as N-methyl-D-aspartate (NMDAR), α-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPAR) and kainite receptors, and metabotropic glutamate receptors. mGluRs can be subclassified into three distinct categories in accordance to sequence homology, G-protein coupling and ligand selectivity: Group I includes mGluR1 and mGluR5, Group II includes mGluR2 and mGluR3, and Group III includes mGluRs 4, 6, 7, and 8
Both long-term potentiation (LTP) and long-term depression (LTD) induction depend on the activation of NMDAR and mGluR (Anwyl, 2009; Gladding et al, 2009; Lüscher and Malenka, 2012) and these receptors can be modulated by extracellular glutamate concentration, which is mediated by glutamate release in the synaptic cleft, glutamate diffusion plus glutamate uptake
Summary
Glutamate was first classified as a neurotransmitter in the 1950s (Hayashi, 1952), and is presently acknowledged as the major excitatory neurotransmitter in the mammalian brain. Glutamate Transporters in Synaptic Plasticity even lead to neural death, by overactivation of NMDA or AMPA receptors in a process referred to as excitotoxicity, suggesting a thorough regulation of its concentration is required for proper neuronal signaling. This regulation is primarily performed by high-affinity glutamate transporters, and by passive diffusion, albeit to a lesser extent (Barbour and Häusser, 1997). There is growing evidences supporting glutamate transporters are not static but extremely dynamic proteins, which can be found internalized in the intracellular space, and when in the membrane, display the ability to diffuse through glia surface (Pita-Almenar et al, 2012; Murphy-Royal et al, 2015), likely shaping the distribution of extracellular glutamate
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