Regulation of Extrasynaptic Glutamate Levels as a Pathophysiological Mechanism in Disorders of Motivation and Addiction

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with an increase in the distance between asymmetric synapses and EAAT2 protein in the frontal cortex in schizophrenia (unpublished observations).

Recent work in a rodent model of heroin relapse provides strong evidence for glutamate spillover as a mechanism of disease. The surface expression and activity of GLT1 (rodent EAAT2) were decreased in the nucleus accumbens core in heroin-dependent rats (Shen et al, 2014). Reinstatement of heroin seeking was inhibited by ceftriaxone, a drug that increases GLT1 protein expression and activity. The authors used a change in the NMDA receptor excitatory postsynaptic current decay time as an index of synaptic glutamate spillover, to demonstrate increased decay in heroin- vs saline-yoked rats (Shen et al, 2014). The increase in decay mimicked the effects of glutamate transport inhibitors in the model, supporting the hypothesis that synaptic glutamate spillover has a central role in relapse and addiction.

The data in schizophrenia and heroin relapse are consistent with findings in depression, where decreased levels of glial transporter expression are reported in brain samples from mood disorder subjects and rodents exposed to chronic stress (Sanacora and Banasr, 2013). Treatment with drugs that increase GLT1 expression and function, including ceftriaxone and riluzole, has antidepressant-like effects in rodent models (Sanacora and Banasr, 2013).

We postulate that diminished perisynaptic glutamate buffering and reuptake may be a common pathophysiological mechanism in psychiatric illness, associated with a number of intermediate phenotypes, including positive (reward learning, reward valuation) and negative (fear, anxiety, loss) valence systems, cognition, arousal and socialization. The diverse biology of the glutamate transporter system, with cell- and splice-variant specific expression regulated by myriad paracrine factors, canonical signaling pathways, exosomal microRNAs, as well as pharmaceuticals such as ceftriaxone, makes it a high yield target that should be exploited for the development of new treatments for a wide array of psychiatric disorders (Lee and Pow, 2010).

FUNDING AND DISCLOSURE

This work was supported by MH087752 (REM), MH094445 (REM), and MH081211 (GS). Dr McCullumsmith declares no conflict of interest. Dr Sanacora has received consulting fees from AstraZeneca, Avanier Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly & Co., Hoffman La-Roche, Merck, Naurex, Noven Pharmaceuticals*, and Takeda over the last 24 months. He has also received additional research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Johnson & Johnson, Hoffman La-Roche, Merck & Co., Naurex, and Servier over the last 24 months. Free medication was provided to Dr Sanacora for an NIH-sponsored study by Sanofi-Aventis. In addition he holds shares in BioHaven Pharmaceutical Holding Company and is a co-inventor on a US patent (#8,778,979) related to the use of glutamatergic drugs in the treatment of neuropsychiatric disorders held by Yale University.