Glutamate and GABA in schizophrenia

Abstract

Schizophrenia is characterized by a loss of brain tissue, which may represent an ongoing pathophysiological process. Possible mechanisms that may be involved are the glutamatergic and GABAergic (gamma-aminobutyric acid) systems. Particularly hypofunction of the N-methyl-D-aspartate (NMDA) type of glutamate receptor may be involved. NMDA-receptor hypofunction leads to insufficient excitatory activity, disrupting the function of GABAergic inhibitory neurons, which in turn may down-regulate their activity. Postmortem studies have indicated reductions in GABAergic neuronal density and receptor binding. The density of neurons expressing glutamic acid decarboxylase (GAD67, the enzyme which catalyzes the conversion of glutamate to GABA) is reduced particularly in the prefrontal cortex in patients with schizophrenia. Meta-analysis of proton magnetic resonance spectroscopy (1H-MRS) studies in patients with schizophrenia reveals that glutamate levels decrease progressively across the illness. Especially young adulthood appears to be a critical period in schizophrenia, both in terms of glutamatergic alterations and cognitive functioning. In healthy young adults, glutamate levels decline with age, which is likely to be due to brain maturation. Hence, glutamatergic anomalies in this age range suggest a disturbed brain maturation. Limitations of prior 1H-MRS studies include the use of relatively low magnetic field strengths (1.5-4T). 1H-MRS at an ultra-high field strength of 7T has the advantages of increased sensitivity and spectral resolution, allowing reliable assessment of glutamate and GABA levels in vivo, especially when using sLASER localization. Using sLASER at 7T, GABA levels decrease in the prefrontal brain region in patients with schizophrenia as compared to matched healthy volunteers, suggesting a loss of synaptic activity that does not seem to be caused by a loss of brain volume. The reduction of prefrontal GABA levels in schizophrenia in vivo is in line with evidence from earlier postmortem studies. The declined prefrontal GABA levels are strongly correlated with the level of cognitive functioning, which suggests a (compensatory) role for GABA through altered inhibitory neurotransmission in the prefrontal cortex may be present in schizophrenia. Also, prefrontal GABA levels do not decline with age irrespective of disease whereas all other brain metabolites do in this relatively young sample, which indicates an important role for GABA in the development of the prefrontal cortex. While glutamate levels are not decreased in patients, probably because of their relatively young age, they do decline with age irrespective of disease in the prefrontal cortex. Interestingly, both the changes in glutamatergic and GABAergic neurotransmission appear to be a pathophysiological component of schizophrenia rather than a consequence of the disease. Furthermore, in healthy individuals working memory performance is associated with lower glutamate and higher GABA levels, hence less excitatory and more inhibitory activity, in the occipital brain region. Since most of the brain’s energy is used for glutamatergic and GABAergic activity, minimizing resources through the excitation-inhibition balance may be beneficial for cognitive functioning. Thus it seems that individuals with a higher intelligent working memory performance make more efficient use of the brain’s energy resources.