A growing body of evidence suggests that changes in glutamate transporter expression may be a factor that is common to many neuropsychiatric disorders. As an example, reduced glutamate reuptake capacity has been linked to a wide variety of conditions such as depression, schizophrenia, and addiction. Mathematical models suggest that under physiological conditions glutamate may diffuse and activate NMDA receptors within a radius of 0.5 μm from the release point (Tzingounis and Wadiche, 2007). Excitatory amino-acid transporters (EAATs) bind and transport glutamate, limiting spillover from synapses due to their dense perisynaptic expression primarily on astroglia. Thus, the spatial arrangement of glutamate synapses, their glutamate transporter buffering zones, and extrasynaptic glutamate receptors will determine the extent and effects of glutamate spillover (Tzingounis and Wadiche, 2007). Increased glutamate spillover may lead to a loss of input specificity, degrading the spatial precision of synaptic transmission. Decreased glutamate spillover, particularly in regions with high levels of physiologic spillover such as the hippocampus, could also disrupt plasticity by limiting spillover transmission. Disruption of glutamate reuptake with genetic models or pharmacological agents yields region- and mechanism-specific phenotypes. For example, the homozygous GLAST (called EAAT1 in the human) KO exhibits locomotor hyperactivity, social withdrawal, and abnormal acoustic startle—deficits analogous to the positive, negative, and cognitive symptoms observed in schizophrenia (Karlsson et al, 2009).

Several postmortem studies found changes in EAAT expression in schizophrenia consistent with diminished regional expression of astroglial (but not neuronal) glutamate transporter expression and activity (Shan et al, 2012). Expression of functional EAAT isoforms appears to be increased in neurons in schizophrenia; we have also found a change in the ultrastructural localization of EAAT2 protein, with an increase in the distance between asymmetric synapses and EAAT2 protein in the frontal cortex in schizophrenia (unpublished observations).

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