Imaging glutamate in schizophrenia: review of findings and implications for drug discovery

Abstract

Currently, all treatments for schizophrenia (SCZ) function primarily by blocking D(2)-type dopamine receptors. Given the limitations of these medications, substantial efforts have been made to identify alternative neurochemical targets for treatment development in SCZ. One such target is brain glutamate. The objective of this article is to review and synthesize the proton magnetic resonance spectroscopy ((1)H MRS) and positron emission tomography (PET)/single-photon emission computed tomography (SPECT) investigations that have examined glutamatergic indices in SCZ, including those of modulatory compounds such as glutathione (GSH) and glycine, as well as data from ketamine challenge studies. The reviewed (1)H MRS and PET/SPECT studies support the theory of hypofunction of the N-methyl-D-aspartate receptor (NMDAR) in SCZ, as well as the convergence between the dopamine and glutamate models of SCZ. We also review several advances in MRS and PET technologies that have opened the door for new opportunities to investigate the glutamate system in SCZ and discuss some ways in which these imaging tools can be used to facilitate a greater understanding of the glutamate system in SCZ and the successful and efficient development of new glutamate-based treatments for SCZ.

NMDA receptor encephalitis and other antibody-mediated disorders of the synapse

“…47,48 An increase in pyramidal activity has also been demonstrated with NMDAR ablation restricted to the frontal pyramidal neurons. 49 Consequently, a decrease of NMDAR function does not implicate a decrease of extracellular glutamate; on the contrary, as a result of a decrease of GABAergic inhibitory activity or signaling pathways modulating NMDAR, there is an increase of extracellular glutamate, as suggested in schizophrenia 47,50 and demonstrated in the frontal cortex and hippocampus of rats after local administration of patients' NMDAR antibodies. 51 …”

The effect of striatal dopamine depletion on striatal and cortical glutamate: A mini-review

“…Undoubtedly the cause(s) of abnormal dopamine-glutamate interactions will differ across neurological and psychiatric disorders. For example, it has been proposed that hypofunctioning of the Nmethyl-D-aspartate (NMDA) receptor may account for the increased glutamate and exacerbated psychostimulant-induced dopamine release observed in schizophrenia patients (Plitman et al, 2014;Poels et al, 2014). Like all working models, the NMDA receptor hypofunctioning model of schizophrenia requires further validation and support (Laruelle, 2014;Laruelle et al, 2005).…”

The role of genetic variation across IL-1β, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain

“…Corticobrainstem glutamate neurons inhibit dopamine release from mesolimbic neurons by signaling through an inhibitory GABA interneuron in the ventral tegmental area (VTA). NMDA hypoactivity within this projection would thus limit these capabilities, and lead to mesolimbic dopamine hyperactivity 81,294 . Indeed, studies show that increased KYNA in schizophrenia leads to hyperactivity of dopamine neurons in the VTA 303 , and administration of NMDA receptor antagonists increases dopamine in the rat nucleus accumbens and striatum 304 .…”

“…Glutamate is the major excitatory neurotransmitter in the CNS, and its dysfunction has been implicated in positive, negative and cognitive symptoms, and changes in brain morphology in schizophrenia 57,203,228,294,302 . Positive Symptoms.…”