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    • These differences have led to

    2022-07-04

    These differences have led to the recognition that the extent to which transport contributes to shaping postsynaptic signals likely reflects a balance between the density of transporters and the amount of l-glutamate in the synaptic cleft. Consequently, those synapses exhibiting the characteristics that would be expected to lead to higher concentrations of l-glutamate in the cleft, such as increased probability of multivesicular release or high-frequency stimulation, should be more sensitive to the inhibition of transport. That this appears to be the case, is supported by studies on a number of such synapses, including those on mossy fibers, cerebellar climbing fibers, retinal bipolar-ganglion cells, and auditory caffeic acid sale stem calyceal cells (Barbour et al., 1994, Kinney et al., 1997, Otis et al., 1997, Higgs & Lukasiewicz, 1999, Matsui et al., 1999, Overstreet et al., 1999, Turecek & Trussell, 2000, Wadiche & Jahr, 2001). In addition to the amount of transmitter released, the concentration of l-glutamate in the cleft should also be a function of the size of the extracellular volume into which it is released. Thus, analogous to high levels of release, transport probably plays a more significant role in shaping postsynaptic signal in synapses with smaller volumes that limit the range of diffusion, such as those securely ensheathed by glial cells. While initial investigations typically focused on the potential of uptake to regulate the amount of transmitter that reaches the postsynaptic receptors in an individual synapse, it has become increasingly evident that transporters are also ideally positioned to control the amount of transmitter that can escape the immediate vicinity of the synaptic cleft and, consequently, activate extrasynaptic receptors. This process has been referred to as “spillover” when transmitter reaches more proximal perisynaptic receptors. A number of studies indicate that metabotropic EAA receptors are often the targets of spillover and that their activation is sensitive to levels of functional transport. Thus, presynaptic inhibition in hippocampal slices and cultures has been shown to be mediated by Group II mGluRs and to be enhanced by transport inhibitors (Scanziani et al., 1997, Vogt & Nicoll, 1999). A similar transporter-sensitive glutamate spillover has also been reported to occur on GABA neurons that are closely apposed to EAA synapses in both the hippocampus and cerebellum, where the activation of presynaptic mGluRs decreases GABA release (Mitchell & Silver, 2000, Semyanov & Kullmann, 2000). Studies further suggest that the glutamate that escapes the synaptic cleft may potentially travel greater distances, enter adjacent synapses, and activate receptors that would normally be silent. For example, experiments with hippocampal CA1 cells, olfactory mitral cells, and cerebellar stellate cells suggest that glutamate leaving a synapse in this manner can activate NMDA and AMPA receptors (Asztely et al., 1997, Isaacson, 1999, Carter & Regehr, 2000, Diamond & Jahr, 2000). While the neurochemical, anatomical, and physiological conditions necessary to support this “crosstalk” is an active area of research, the actions of uptake blockers suggest that transporter density may be a determining factor. In the same way that transport inhibitors are being used to evaluate the role of the EAATs in signal termination, they have also been employed to assess the role of the transporters in regulating potentially pathological levels of glutamate and protecting neurons from excitotoxic injury. As the extracellular concentration of glutamate accessible to EAA synapses become excessive, it leads to the over-activation of ionotropic EAA receptors and the triggering of a number of pathological cascades including both osmotic- and calcium-dependent pathways (for review, see Choi, 1994, Rothman & Olney, 1995, Olney, 2003). Accumulating evidence indicates that excitotoxicity contributes to neuronal pathology associated with both acute CNS injury (e.g., stroke, head trauma, spinal cord injury) and chronic neurodegenerative diseases (e.g., ALS, Alzheimer's, Parkinson's and Huntington's disease). Not surprisingly, it is hypothesized that there should be an inverse relationship between transport capacity and the likelihood that extracellular glutamate will increase to levels that become pathological. Uptake blockers therefore provide a pharmacological approach to compromise transporter activity and evaluate the effect on vulnerability of neurons to excitotoxic injury.