Professor Daniel Weinberger discusses evidence from a number of research areas that highlight the importance of the neurotransmitter glutamate in schizophrenia.

So how does glutamate relate to schizophrenia? For probably forty years, most of the work on schizophrenia was focused on dopamine. But because the evidence has increasingly centered around areas of the brain like the frontal lobe and the hippocampus, which are the so-called cortical regions of the brain, there’s been a lot more interest in what are the neurotransmitters that are critical for how the cortex works. And in the cortex, the main neurotransmitters are amino acid neurotransmitters like glutamate and GABA. Glutamate is the principle neurotransmitter of cells that communicate across long distances in the brain. Such as across cortical regions and from the cortex down into the spinal cord or out into the rest of your body. And glutamate is a critical molecule for the function of the cortex. Based on those observations, there’s been a lot of research to look at glutamate. And there’s a pharmacological model of schizophrenia based on the blocking of certain glutamate receptors, a particular glutamate receptor called the NMDA receptor, which is the N-methyl-D-aspartate receptor. There’s a drug, a street drug, called PCP which blocks this receptor. Associated with the use of this drug is a psychotic-like state – not just a psychotic state but also change in cognitive function, change in the ability to pay attention, distraction which have certain features of schizophrenia. So there’s been a pharmacological model of schizophrenia based on glutamate. Turns out, so far, most of the genes that have been found that relate to schizophrenia, particularly neuregulin, dysbindin, COMT – some other genes like GRM3, AKT1, calcineurin, etc. – many of these genes seem to impact on the function of glutamate in the brain. So glutamate might be a final common pathway that many of the biological risk factors impact upon to translate into the kind of behavior and brain function we see in schizophrenia.

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