SLC7A11, the catalytic subunit of the cystine/glutamate antiporter, System x _c ⁻ (SXC), is up-regulated in a subpopulation of patient gliomas, where it is responsible for excitotoxic glutamate release, accelerated tumor growth, and tumor-associated seizures.

The glutamate system is complex; it includes multiple modulating cotransmitters, interacting receptors, and multisystem synapses. The regional characteristics of neuronal architecture, local circuitry, and signaling mechanisms suggest that important aspects of glutamate metabolism are modulated at a local level.¹ Imbalances in glutamatergic neurotransmission and metabolism are proposed as key pathomechanisms in schizophrenia.^1,2N-methyl-d-aspartate receptor hypofunction on γ-aminobutyric acid neurons could result in disinhibition of postsynaptic glutamate neurons, excessive glutamate release, and neurotoxicity. Although excitotoxicity may not be the cause of schizophrenia, it could contribute to the course of the disorder (see Konradi and Heckers³).

Recent magnetic resonance spectroscopy (MRS) studies suggest that abnormalities of the glutamatergic system in schizophrenia may be dependent on illness stage, medication status, and symptomatology. Glutamatergic metabolites appear to be elevated in the prodromal and early stages of schizophrenia but unchanged or reduced below normal in chronic, medicated patients. However, few of these studies have measured metabolites with high-field 7T MR scanners, which offer higher signal-to-noise ratio and better spectral resolution than 3T scanners and facilitate separation of glutamate and glutamine into distinct signals. In this study, we examined glutamate and other metabolites in the dorsal anterior cingulate cortex (ACC) of first-episode schizophrenia patients. Glutamate and N-acetylaspartate (NAA) were significantly lower in schizophrenia patients vs controls. No differences were observed in levels of glutamine, GABA, or other metabolites. In schizophrenia patients but not controls, GABA was negatively correlated with the total score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as well as the immediate memory and language subscales. Our findings suggest that glutamate and NAA reductions in the ACC may be present early in the illness, but additional large-scale studies are needed to confirm these results as well as longitudinal studies to determine the effect of illness progression and treatment. The correlation between GABA and cognitive function suggests that MRS may be an important technique for investigating the neurobiology underlying cognitive deficits in schizophrenia.

A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, P_FDR<0.05, k_E=2198, x=−30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, P_FDR<0.05, k_E=6094, x=−28, y=−36, z=−2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.