The Underlying Neural Circuitry of Schizophrenia

Dr Andrew Cutler: Hello, I am Dr. Andrew Cutler, clinical associate professor of psychiatry at SUNY Upstate Medical University in Syracuse, New York. And I am the Chief Medical Officer for the Neuroscience Education Institute in Carlsbad, California. And my practice is actually based in Lakewood Ranch, Florida. 

Amber Hoberg: I'm Amber Hoberg. I'm a psychiatric mental health nurse practitioner. I practice at Baptist Healthcare System and Morningstar Family Medicine in San Antonio, Texas. 

Dr Andrew Cutler: Most of us know that schizophrenia is a neurodegenerative and neuroprogressive illness, and we actually have abundant evidence now with neuroimaging studies that show that people with schizophrenia have a significantly reduced gray matter volume in the brain, literally a shrinkage of the brain, compared to those who don't have schizophrenia. And what you see here are some renderings going from left to right, from ages 25 up to 55, and the colored areas represent areas that have more shrinkage in the gray matter in the patients with schizophrenia versus those who don't have schizophrenia. This is really concerning, I'll be honest, because this is correlating with cognitive impairment with reduced brain function. And this, of course, as we know, correlates with their problems functioning over time. We know that relapse is bad for the brain, and it is probably accelerating this process, which may already be happening. And so we really want to work hard, at least to prevent relapse, to try to prevent some of this from happening. 

I had a very wise professor, and I trained in an era before we had a lot of the modern neuroimaging techniques, and he used to say to us, “Never let a patient stay psychotic because psychosis is bad for the brain.” And here we certainly have evidence of that. Well, we know that dopamine is certainly involved in the pathophysiology of schizophrenia. And as a matter of fact, there's clear evidence of disruptions in certain dopamine circuitry. So let's review now some of the dopamine circuits that we think are relevant. And Amber, we've recently learned that the classic dopamine pathways we were taught are not exactly accurate because they were based on studies of rodents. Newer technology has allowed us to look at the human brain and to understand now that there are three really relevant dopamine pathways here. The first one projecting to the upper left is called the mesocortical pathway from the midbrain, specifically the ventral tegmental area, where dopamine cell bodies live, up to the prefrontal cortex. And we believe there's too little dopamine activity in that pathway, and that's causing cognitive impairment. 

So, our goal is to try to increase activity in that region. The pathway we used to be told was called the mesolimbic pathway, but it turns out it's not really mesolimbic because it's not the ventral tegmental area—it's actually the nigrostriatal pathway. And the nigrostriatal pathway, we think, divides into a couple of areas. One is the classic mesolimbic projection into the limbic system and the ventral striatum. We think that is underactive. There's not enough dopamine activity there, and that leads to negative symptoms. So, our goal is to get more activation in that circuit. And finally, we have the nigrostriatal pathway going to the associative part of the striatum. So, actually, we believe now, dopamine activity is too high going to a part of the striatum that's coming from substantia nigra. We used to think the mesolimbic was the ventral tegmental to the ventral striatum and the limbic system. So here we have too much dopamine going to the associative striatum. This causes the positive symptoms. And of course, our goal is to reduce this. Now it turns out we've learned that this is not just a dopamine problem. We have learned that there are abnormalities in an NMDA, a glutamate NMDA receptor, on a GABA interneuron in the prefrontal cortex. Oh my goodness, that's a lot. 

Amber Hoberg: Say that 10 times fast. 

Dr Andrew Cutler: Say it 10 times fast. So what we think is happening here is that we are interfering with or influencing a descending glutamate pathway. So, there are pyramidal glutamate neurons that start in the prefrontal cortex and project down into the midbrain, specifically where the dopamine cell bodies live. And so dopamine, being the excitatory neurotransmitter, think of it like the gas pedal, if there's too much glutamate activity, that's going to overdrive dopamine activity, especially into that associative striatum, when we think that that's the problem with positive symptoms. Okay, so if this glutamate NMDA receptor isn't working properly, maybe we can figure out ways to help it to work properly. First, we need to understand this NMDA receptor. There are many glutamate receptors. There are a couple of them that are ion channel receptors, and some of them are metabotropic, classic kinds of second messenger receptors. 
The relevant glutamate ion channel receptors are NMDA and AMPA. But let's focus on NMDA. Notice this is an ion channel, and a couple of things, actually, three things have to happen to activate this. When you activate this receptor, the channel opens, and we see ions flowing through sodium and calcium. But what's preventing that from happening is there is a magnesium plug sitting in that channel. So the first thing you have to do is remove the magnesium plug. Next, you have glutamate binding to its receptor-binding site on the NR2 subunit. And you can see those are purple triangles. But also at the same time, to fully activate this receptor, you need something else to bind. You need what's called a co-agonist. In this case, it's glycine. So, you remove the magnesium plug, glutamate binds, then glycine binds, and notice they're on two different subunits of the NMDA receptor. 

And that opens the channel. You get a burst of glutamate and we think then good things happen within the cell. There's many lines of evidence that this receptor’s involved with the pathophysiology of schizophrenia. And, in particular, we have animal models showing that hypofunction of that receptor, again on a glutamate interneuron, underlies the pathophysiology, both positive, negative, and cognitive impairment in schizophrenia. 

Amber Hoberg: Thank you so much for joining and watching today. 

Dr Andrew Cutler: And for more information, please check out Psych Congress Network.