Glutamate Transporters in Hippocampal LTD/LTP: Not Just Prevention of Excitotoxicity

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.

Keywords: NMDAR; astrocytes; glutamate transporters; synaptic plasticity; tripartite synapse.

FIGURE 1

Glutamate transporters have the ability to monitor the concentration of synaptic glutamate, potentially controlling the activity of glutamate metabotropic and ionic receptors. (A) During LTP induction there is an increase of glutamate transport activity probably due to an increase of glutamate transporters near synaptic cleft. This can be due to a intracellular trafficking from the intracellular space to the membrane and surface diffusion to the synaptic region, leading to an optimal activation of postsynaptic receptors. (B) As for LTD induction, the specific role of glutamate uptake is yet to be revealed. It is know that increase of glutamate transporters decreases LTD, perhaps by not activating postsynaptic receptors to an optimal level. Furthermore, blockade of glutamate uptake enhances LTD suggesting that glutamate uptake may not be static during this phenomenon. We propose that there occurs some sort of glutamate uptake decrease either by removing glutamate transporters by internalization or by surface diffusion.