Schizophrenia: Stigma, GABA, and MRS

Why is it that so many people talk openly about their struggles with diabetes, heart disease, or arthritis, while mental illness is often whispered about or kept hidden within families?

Part of the stigma comes from the obvious fact that mental illnesses affect the brain, which we know a lot less about than the pancreas, heart, bones, or cartilage—and which we associate with our behaviors and personality traits. But brain tumors also damage the brain, and have the potential to impact how we think or act. Yet there’s a lot less secrecy surrounding brain tumors than there is around schizophrenia.

One of the key differences is our ability to see and measure the pathology. Brain tumors are routinely imaged and described in radiology reports, with stats on size and location. With a biopsy, individual tumor cells can be analyzed under a microscope and the type of brain cancer can be determined. By comparison, the structural or biochemical changes in the brain that underlie schizophrenia remain a mystery. There is no biologically-based method of diagnosis.

Fortunately, neurobiologists are hard at work trying to uncover the cellular and molecular pathologies in schizophrenia. An important piece in the puzzle seems to be the dysfunction of the GABA system—the major inhibitory neurotransmitter system of the brain. It is hypothesized that abnormalities in the levels of GABA and the neurons which secrete it contribute to the disease process in schizophrenia.

Magnetic resonance spectroscopy (MRS) is one of the tools allowing researchers to begin testing this, and other hypotheses involving alterations in brain metabolites, in living humans. At Tuesday night’s Conte-CBS Colloquium on Mental Health, Dost Ongür, MD, PhD, Chief of the Psychotic Disorders Division at McLean Hospital, will discuss MRS studies on the neurobiology of schizophrenia.

Below are some background questions and answers about the GABA dysfunction hypothesis and MRS:

Where did the GABA dysfunction hypothesis in schizophrenia come from?

While the nature of GABA dysfunction in schizophrenia is complex and remains an active area of investigation, the evidence that there is some sort of GABA dysfunction is pretty compelling and longstanding. Nearly two decades ago, it was discovered that people with schizophrenia have reduced mRNA levels of GAD67 in prefrontal cortex. GAD67 is one of two important enzymes that make GABA. As Lewis et al. note in their review of cortical inhibitory neurons and schizophrenia, the GAD67 finding has been reproduced several times and is one of the most consistent results in postmortem studies of schizophrenia.

Further supporting the idea of GABA dysfunction are expression profiling studies and genetic analyses. The expression of a number of GABA-related genes—the “GABA-related transcriptome”—tends to be diminished in the prefrontal cortex of individuals with schizophrenia. These genes encode peptides released by GABA neurons, components of GABA receptors, and a molecule that transports GABA. In addition, in the hippocampus, molecules controlling the maturation of GABA signaling have altered expression patterns. Also, specific variants of the GAD67 gene and other genes regulating inhibitory neural activity are found more frequently in individuals with schizophrenia.

Beyond such postmortem or genetic analyses, experiments measuring brain activity in living people with schizophrenia have revealed impairments in the inhibitory activity of the cortex. These defects were measured using transcranial magnetic stimulation, a non-invasive technique where magnetic fields are used to manipulate the electrical activity of brain cells.

Does this connect to the E/I balance hypothesis for mental illness in general?

Yes. Particularly vulnerable in schizophrenia are GABA interneurons that make the calcium-binding protein parvalbumin (PV cells). While the number of PV cells is not substantially altered, PV cells seem to bear the brunt of the GAD67 decrease and display other significant changes in gene expression. The impairment of PV cells is important because PV cells regulate the firing patterns of excitatory pyramidal neurons in the cortex and hippocampus and their activity is thought to play a key role in establishing the brain’s excitatory/inhibitory (E/I) balance.

Besides GABA, a number of neurotransmitter systems are disrupted in schizophrenia. These include the glutamatergic, cholinergic, and dopaminergic systems. In their circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia, Lisman et al. brainstorm ways that GABA dysfunction may be linked to defects in these other neurotransmitter systems. Central to their model are studies suggesting that one category of glutamate receptors—the NMDA type glutamate receptors—function inadequately in schizophrenia. The NMDA receptors of PV cells in particular may be a key site of dysfunction.

What is MRS? What have MRS studies of GABA levels in individuals with schizophrenia revealed?

MRS is a technique related to magnetic resonance imaging (MRI). While MRI gives us anatomic images of the brain, MRS can provide quantitative information about the levels of various brain metabolites. By providing a safe, non-invasive way to examine the brains of living human beings, magnetic resonance-based tools in general have significantly advanced our understanding of psychiatric disorders over the past three decades.

One way to test the GABA dysfunction hypothesis is to measure the levels of GABA in individuals with schizophrenia using MRS. So far, as Alison Curley describes on the Schizophrenia Research Forum, the results of such studies have been confusing—with two groups finding an elevation in GABA, two finding a decrease, and one observing no change.

In 2009, Goto et al. reported a reduction in GABA levels in the basal ganglia of early-stage schizophrenia patients, but not in the frontal or parieto-occipital lobes. In 2010, three groups published. Tayoshi et al. looked in the anterior cingulate cortex and left basal ganglia of chronic schizophrenia patients and found no overall change in the concentration of GABA. Yoon et al. looked in the visual cortex of a mix of chronic and recent-onset schizophrenia patients and found a reduction in GABA concentration. In contrast, Ongur et al. looked in the anterior cingulate cortex and parieto-occipital cortex of chronic schizophrenia patients and, surprisingly, found an elevation in GABA levels in both areas. The latest study, published last month by Kegeles et al., also found an elevation in GABA levels. This elevation was observed in the medial, but not dorsolateral, prefrontal cortex.

What could be producing these different MRS results?

First and most obvious, everyone is not looking in the same brain region. Second, the medication status of the patients is a key variable. The Kegeles et al. study was the first in this series to examine a cohort of non-medicated patients. The reported elevation of GABA in the medial prefrontal cortex in this study was not observed in a comparison group of patients treated with antipsychotics. Also, Ongur comments that factors such as the stage of the illness or other types of medications that patients may concurrently be taking, such as anticonvulsants, could be contributing to the different findings.

Studying larger sets of patients and having more detailed phenotypic information about the nature of each patient’s schizophrenia may help to clarify the MRS findings. Another key concept to keep in mind when thinking about these MRS findings, as Curley and Ongur both point out, is that the total tissue levels of GABA are being measured. So it would be entirely possible to find elevated GABA levels in a brain region by MRS, yet have reduced GABAergic transmission at synapses within that region.