DNA Degradation in Schizophrenia and Bipolar Disorder
1 March 2012. Neurons from individuals with schizophrenia and bipolar disorder harbor genomic copy number differences that are circuit- and diagnosis-specific, according to a study published online February 6 in Archives of General Psychiatry. Led by Francine Benes of McLean Hospital in Belmont, Massachusetts, the study suggests that abnormal losses or gains of DNA segments can accumulate in mature neurons, leading to their malfunction.
The findings provide a first glimpse of the state of the DNA within neurons in these disorders, and suggest that some malleability is present. Recent genetic studies have offered up copy number variants (CNVs)—deletions or duplications of DNA segments—as potential causal factors for psychiatric disease (see SRF related news story; see SRF related news story). However, the copy number changes identified by Benes and colleagues are proposed to lie downstream of causal factors, arising instead in fully mature neurons later in life and possibly driving the specific brain dysfunction found in schizophrenia and bipolar disorder.
“Now we may have a basis for understanding dysfunction in terms of genomic integrity,” Benes told SRF. “When we see the amount of genomic integrity that has been changed, the critical question may be, How much dysfunction is that really related to?”
There's something about GAD67
One consistent marker of altered brain function found in postmortem brain samples from people with schizophrenia and bipolar disorder has been the decreased expression of glutamate decarboxylase (GAD67), an enzyme that produces γ-aminobutyric acid (GABA). This has led to various lines of research on possible GABAergic dysfunction in schizophrenia (see SRF related news story). Trying to understand why there should be such a deficit in GAD67, Benes and colleagues published a gene expression profiling study in 2007 in which they turned up a network of genes involved in GAD67 regulation, as well as neurogenesis, cell cycle, and DNA repair (see SRF related news story). Though these last processes are more appreciated in proliferating cells, they may also be critical for protecting the genome in a fully mature neuron—an idea that casts the postmitotic, differentiated neuron as a state that is actively maintained, rather than a static endstage.
The new study asked whether any telltale signs of genomic degradation could be found in the brain, and whether they were associated with a particular diagnosis and cell type. The researchers focused on the stratum oriens of the hippocampus, which contains exclusively GABAergic cells and exhibits the GAD67 deficits in schizophrenia and bipolar disorder. Building on previous work showing distinct patterns of gene expression in these cells, depending on whether they were in the CA3/2 or CA1 region of the hippocampus (see SRF related news story), the team compared copy number measures across these circuits, as well as across diagnoses.
Copy number intensities
First author Guoqing Sheng and colleagues used laser microdissection to excise the stratum oriens from CA3/2 and CA1 in postmortem brain samples from 15 individuals with schizophrenia, 15 with bipolar disorder, and 15 controls. The DNA from these samples was probed with a single nucleotide polymorphism microarray, which can reveal changes in copy number of DNA segments by changes in signal intensity. The researchers did a targeted search for these irregularities, analyzing only those SNPs tagging the 28 previously identified as belonging to a GAD67 regulatory network.
In CA3/2, the researchers detected a decrease in copy number intensity of the GAD67 gene in schizophrenia samples, suggesting some loss of that gene. Specifically, the mean copy number intensity was 1.68 in schizophrenia, compared to 2.16 in controls—a difference amounting to a 22 percent decrease. In bipolar disorder, a 25 percent decrease was measured. In CA1, the story was somewhat similar, with a 27 percent decrease in schizophrenia compared to controls, but no significant decrease for bipolar disorder.
Looking across all 28 genes, CA3/2 emerged as a hotspot of genomic degradation: in schizophrenia samples, 15 of the 28 genes showed significant differences in copy number intensities compared to controls, and in bipolar samples, 18 out of 28 genes showed this. In contrast, in CA1, only 10 out of 28 genes showed significant changes in schizophrenia, and only three out of 28 in bipolar samples.
These patterns differed between disorders. Among the genes specifically involved in GAD67 regulation, the researchers pinpointed copy number intensity changes in five genes (HDAC11, DAXX, PAX5, RUNX2, and CCND2) that were similar in magnitude and direction to those reported in their gene expression profile study in 2007. In CA3/2, schizophrenia samples had a marked increase in HDAC11, a histone deacetylase involved in epigenetic regulation, and DAXX, a transcription regulator, whereas bipolar samples did not. Conversely, bipolar samples exhibited decreases in copy number intensity for RUNX2, a transcription factor involved in cell differentiation, and CCND2, a crucial cyclin that regulates the cell cycle, whereas schizophrenia samples showed no change in these compared to controls. These results suggest that the decrease in GAD67 expression shared by schizophrenia and bipolar disorder may be brought about by distinct molecular mechanisms.
Copy number differences were also detected in CA3/2 among neurogenesis-related genes, including an increase in intensity in growth factor-encoding VEGF and a decrease in NRG1 in schizophrenia, and increases for both in bipolar samples. Among cell cycle and DNA repair genes, a copy number reduction in transcription factor E2F3 was detected in schizophrenia, and increases in a DNA repair enzyme MBD4 emerged for both schizophrenia and bipolar; these kinds of changes were not so apparent in CA1.
Local context matters
Asking whether these genomic irregularities were associated with gene expression, the team found robust correlations between copy number intensity and corresponding mRNA levels obtained in their previous study. Within CA3/2, significant positive correlations were found for schizophrenia (r = 0.649, p = 0.0003) and bipolar disorder (r = 0.772, p = 0.0002). However, no correlations were found within CA1, which the authors propose may be due to local environment influences on transcriptional regulation (see SRF related news story). Differences in local circuitry may also explain why CA3/2 is a hotspot for genomic degradation compared to CA1. Stratum oriens neurons in CA3/2, but not CA1, receive input from the basolateral amygdala, a region noted for mediating emotional responses, and studied in the context of psychiatric illness. Benes proposes that synaptic activity from this input could promote oxidative stress in the already highly active GABAergic cells, and trigger a cascade of molecular changes, including DNA damage. Her team is now exploring this idea in rat hippocampus (e.g., Gisabella et al., 2009).
The results reveal a complicated checkerboard of gene-, circuit-, and diagnosis-specific DNA changes, and suggest that a subtler kind of genomic degradation lying somewhere between the cell death of neurodegenerative disorders and the rampant cell proliferation driving cancer may be at work in psychiatric illness. As future research discerns whether, and how much, these kinds of changes contribute to psychiatric illness, it will be important to keep in mind the cellular context of a given genetic glitch. “We have to be cautious about extrapolating from a particular anatomic locus to different parts of the brain,” Benes said.—Michele Solis.
Sheng G, Demers M, Subburaju S, Benes FM. Differences in the Circuitry-Based Association of Copy Numbers and Gene Expression Between the Hippocampi of Patients With Schizophrenia and the Hippocampi of Patients With Bipolar Disorder. Arch Gen Psychiatry. 2012 Feb 6. Abstract
Comments on Related News
Related News: Genetics, Expression Profiling Support GABA Deficits in SchizophreniaComment by: Karoly Mirnics, SRF Advisor
Submitted 26 June 2007
Posted 26 June 2007
The evidence is becoming overwhelming that the GABA system disturbances are a critical hallmark of schizophrenia. The data indicate that these processes are present across different brain regions, albeit with some notable differences in the exact genes affected. Synthesizing the observations from the recent scientific reports strongly suggest that the observed GABA system disturbances arise as a result of complex genetic-epigenetic-environmental-adaptational events. While we currently do not understand the nature of these interactions, it is clear that this will become a major focus of translational neuroscience over the next several years, including dissecting the pathophysiology of these events using in vitro and in vivo experimental models.
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Related News: Genetics, Expression Profiling Support GABA Deficits in Schizophrenia
Comment by: Schahram Akbarian
Submitted 26 June 2007
Posted 26 June 2007
I recommend the Primary Papers
The three papers discussed in the above News article are the most recent to imply dysregulation of the cortical GABAergic system in schizophrenia and related disease. Each paper adds a new twist to the story—molecular changes in the hippocampus of schizophrenia and bipolar subjects show striking differences dependent on layer and subregion (Benes et al), and in prefrontal cortex, there is mounting evidence that changes in the "GABA-transcriptome" affect certain subtypes of inhibitory interneurons (Hashimoto et al). The polymorphisms in the GAD1/GAD67 (GABA synthesis) gene which Straub el al. identified as genetic modifiers for cognitive performance and as schizophrenia risk factors will undoubtedly spur further interest in the field; it will be interesting to find out in future studies whether these genetic variants determine the longitudinal course/outcome of the disease, treatment response etc etc.
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Related News: GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects
Comment by: Dost Ongur
Submitted 19 January 2012
Posted 19 January 2012
This news story by Allison Curley cogently and succinctly describes the current state of affairs in studies of parenchymal GABA levels in schizophrenia. Measuring GABA in vivo in the human brain has been challenging because this metabolite exists in relatively
low concentration and its signal overlaps with that of other, more abundant
metabolites. The literature has grown recently with the advent of higher-field
MRI scanners and reliable MRS approaches for GABA measurement.
As outlined in the story, the several papers on parenchymal GABA
levels in schizophrenia are about evenly split, with reductions and elevations
both being reported. Although MRS is characterized by a relatively low
signal-to-noise ratio and high variance in most datasets, all the recent studies
used reliable MRS techniques such as MEGAPRESS.
In my opinion, the current state of the literature offers two insights:
1. If there was a significant and consistent abnormality in parenchymal GABA
levels in schizophrenia, we would have found it and the studies would agree.
Rather, it appears that there may be patient and treatment factors leading to
differential GABA patterns. For example, to speculate: elevations in early illness
may be replaced by reductions with chronic disease, or anticonvulsants may elevate GABA levels while antipsychotics reduce them. Larger datasets with more detailed
phenotypic analyses may provide leads for developing a clearer picture.
Alternatively, and less interestingly, there may be no or minor abnormalities which
result in conflicting findings due to sampling error, technical differences, etc.
2. As a corollary to any of the possibilities above, it is clear that abnormal
GABAergic neurotransmission is not necessarily associated with consistently
reduced parenchymal GABA levels as measured by MRS. Postmortem and other lines
of evidence are quite convincing of abnormalities in GABAergic interneurons in
schizophrenia. However, the in-vivo MRS studies are much less consistent,
suggesting a disconnect between the two lines of inquiry. Just to describe one
possibility, it is possible that GABA is inappropriately stored in synaptic
vesicles instead of being released into the synapse and subsequently
metabolized, setting up elevated GABA levels but reduced GABAergic
Although confusing at the moment, the optimistic view is that MRS studies of
brain GABA levels in schizophrenia will ultimately offer a more sophisticated
understanding of the relationship between metabolite levels measured using MRS
and the brain functions we all care about.
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Related News: GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects
Comment by: Jong H. Yoon, Richard J. Maddock
Submitted 8 February 2012
Posted 8 February 2012
The study by Kegeles et al. has added unique and important findings to the small but rapidly growing literature assessing in-vivo GABA levels in schizophrenia using MRS. In the context of these studies, the Kegeles publication also raises several challenging questions regarding the potential relevance and reliability of in-vivo GABA studies. Here, we would like to comment on two of these questions. The first pertains to the lack of convergence with the consistent postmortem studies. The second is the apparent lack of consistency across the recent in-vivo GABA studies in schizophrenia.
A starting point in the discussion of the first issue is to recognize the differences in what we are measuring with in-vivo spectroscopy as opposed to the postmortem studies. The latter have consistently demonstrated decreased mRNA levels for GAD67, one of the major synthetic enzymes for GABA, in a subset of GABAergic interneurons in the neocortex of schizophrenia. Based on this postmortem work and the important role GAD67 plays in determining whole cell content of GABA (Asada et al., 1997), many, including Kegeles and coauthors, had predicted MRS measurements of GABA would be decreased in schizophrenia. Spectroscopy measures bulk GABA, the largest fraction of which is cytoplasmic and not vesicular. The cytoplasmic fraction of GABA is synthesized by GAD67 (abnormal in postmortem studies of schizophrenia), while the vesicular fraction is synthesized in part by GAD65 (not apparently abnormal in schizophrenia) (Waagepetersen et al., 2007). While vesicular GABA is the source of GABA for synaptic neurotransmission, cytoplasmic GABA may play a role in both tonic and phasic inhibition mediated by extrasynaptic GABAergic signaling (Wu et al., 2007). One of the major limitations of MRS measurements of GABA, therefore, is that we currently do not really understand to what extent this bulk measurement relates to neural signaling. However, there are a growing number of studies (Edden et al., 2009; Sumner et al., 2010), including one by our group (Yoon et al., 2010), that suggest that bulk GABA measurement is a functionally meaningful measure. These studies have shown high correlations between MRS estimates of GABA and performance on tasks presumably dependent on the magnitude of GABA-mediated inhibition. In addition, animal studies have suggested that the concentrations of vesicular and non-vesicular pools of GABA appear to be in equilibrium (Waagepetersen et al., 1999), implying that bulk GABA levels reflect, to some degree, the vesicular fraction. Nonetheless, as others have pointed out, the diverse components of the GABA MRS measurements leave open a number of potential explanations as to why bulk GABA levels may not be decreased in schizophrenia in the setting of decreased GAD67 mRNA levels.
The second set of questions concerns the apparent lack of consistency among the recent set of in-vivo GABA studies. The potential reasons for this are many and diverse, and include clinical and neuroimaging-related factors that may have varied across the spectroscopy studies, including differences in illness severity, length of illness, brain regions assessed, and methods for GABA quantification. The Kegeles paper has identified medication status as an important clinical variable for which future studies should attempt to account. In-vivo GABA spectroscopy using MEGA PRESS is a relatively new method, particularly as applied to between-group studies. Consequently, there may be a number of neuroimaging-related variables that are important sources of noise or diminished signal, leading to false-negative findings of group differences, or bias, leading to false-positive findings of group differences. An example of the former relates to the phased array head coils frequently used in GABA studies. With these receive-only coils, signal strength decreases linearly as a function of the distance between the coil element that detects the spectroscopy signal and the brain region being sampled. Thus, the signal from brain regions farther away from these elements, for example, deep midline and subcortical regions, will be much lower than regions that are adjacent to these elements, for example, the occipital pole. Consequently, our ability to detect true differences between groups in these low-signal regions will be constrained. Another important variable may be in-scanner head movement. From our own work, we are coming to believe that in-scanner head movement may produce significant over- or underestimation of true GABA concentration, depending on the type of movement. The effect of head movement may be particularly important in between-group studies in which one group may exhibit a significantly different amount of movement compared to the other group. Even a few patients with excessive movement during a prolonged MRS acquisition could generate outlying and erroneous GABA values and lead to false-positive group differences.
In summary, we are in the very early stages of MRS studies of GABA in schizophrenia. There are many unanswered questions regarding the meaning of this signal and how it relates to GABA physiology, function, and their impairment in schizophrenia. The answers to these questions will require intense efforts relying on animal and human models to unravel the complex relationships between bulk GABA measurements and GABA signaling. As a methodology, much more work needs to be done to validly and reliably translate this method to clinical studies. In the immediate future, it will be critical to identify the important sources of noise and bias, and to develop methods controlling for these variables in clinical studies so that the true nature of GABA levels in schizophrenia may be established.
Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N, et al (1997): Cleft Palate and Decreased Brain Gamma-aminobutyric Acid in Mice Lacking the 67-kDa Isoform of Glutamic Acid Decarboxylase. Proc Natl Acad Sci U S A 94:6496-6499. Abstract
Edden RAE, Muthukumaraswamy SD, Freeman TCA, Singh KD. (2009) Orientation Discrimination Performance Is Predicted by GABA Concentration and Gamma Oscillation Frequency in Human Primary Visual Cortex. Journal of Neuroscience 29(50):15721-15726. Abstract
Sumner P, Edden RAE, Bompas A, Evans JC, Singh KD (2010) More GABA, Less Distraction: a Neurochemical Predictor of Motor Decision Speed. Nature Neuroscience 13:825-827. Abstract
Waagepetersen HS, Sonnewald U, Larsson OM, Schousboe A. (1999) Synthesis of Vesicular GABA From Glutamine Involves TCA Cycle Metabolism in Neocortical Neurons. Journal of Neuroscience Research 57:342-349. Abstract
Waagepetersen HS, Sonnewald U, Schousboe A (2007) Glutamine, Glutamate, and GABA: Metabolic Aspects. In: Lajtha A, Oja S, Schousboe A, Saransaari P (eds) Handbook of Neurochemistry and Molecular Neurobiology: Amino Acids and Peptides in the Nervous System. Springer, New York, pp 1-21.
Wu Y, Wang W, Diez-Sampedro A, Richerson GB (2007) Nonvesicular Inhibitory Neurotransmission Via Reversal of the GABA Transporter GAT-1. Neuron 56:851-865. Abstract
Yoon JH, Maddock RJ, Rokem AS, Silver MA, Minzenberg MJ, Ragland JD, Carter CS. (2010) Gamma-aminobutyric Acid Concentration is Reduced in Visual Cortex in Schizophrenia and Correlates with Orientation-Specific Surround Suppression. Journal of Neuroscience 10;30(10):3777-81. Abstract
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Related News: GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects
Comment by: Robert McCarley, Margaret Niznikiewicz, Martina M. Voglmaier, Kevin Spencer (Disclosure), Nick Bolo, Alexander P. Lin, Youji Hirano, Elisabetta DelRe, Israel Molina, Vicky Liao, Sai Merugumala
Submitted 13 February 2012
Posted 14 February 2012
I recommend the Primary Papers
The important and elegantly controlled work by Kegeles et al., and the informed comments of Ongur, Yoshimura, and Yoon and Maddock, on GABA in schizophrenia raise a series of potentially key factors about the sources of variability of MRS findings in this disorder (medication, stage of illness, and region of interest [ROI]). They also point out the need for association of MRS GABA findings with physiologic measures such as γ oscillations (40 Hz), a functional measure particularly relevant because of the involvement of GABA interneurons interacting with pyramidal neurons in generating this oscillation.
We would like to call the reader's attention to a potentially informative schizophrenia spectrum disorder, schizotypal personality disorder (SPD), that may help shed light on and respond to these issues. As has been documented by Kendler (Kendler et al., 1993; Fanous et al., 2007), SPD shares a genetic relationship with schizophrenia. Although sharing the symptoms of schizophrenia, SPD individuals have an attenuated version of the symptoms and are not psychotic. One thus can recruit SPD individuals who are living in the community, have never been neuroleptic medicated, who have no current medication, and who do not show the profound lifestyle disturbance of individuals with schizophrenia.
We have begun MRS evaluations on SPD subjects with these characteristics, choosing ROI in the superior temporal gyrus (STG) because of the strong evidence of the association of this region with the auditory steady-state (ASSR) γ oscillation response, as well as structural MRI evidence for left STG reduced gray matter volume. Our still quite preliminary data showed, compared with matched healthy controls, a mean reduction in GABA levels and an increase in glutamate. Although the levels were not yet statistically significantly different in our preliminary data, what was notable, and statistically significant, was the very high correlation of the left STG glutamate and GABA levels with the levels of the ASSR γ oscillation, measured as the strength of the phase locking factor (PLF) over left-sided electrodes. As predicted, GABA levels were positively correlated with the PLF, while glutamate levels were inversely (negatively) correlated with the PLF. Obviously, more data are needed, but these initial findings suggest the promise of using SPD subjects with both MRS and γ oscillation measurements in the STG.
Preliminary results to be presented at the 3rd Biennial Schizophrenia International Research Society Conference 14-18 April 2012, Florence, Italy, as a poster and an oral presentation, and at the 20th Annual Meeting of the International Society of Magnetic Resonance in Medicine 5-11 May 2012, Melbourne, Australia.
Kendler KS, McGuire M, Gruenberg AM, O'Hare A, Spellman M, Walsh D. (1993). The Roscommon Family Study. III. Schizophrenia-related personality disorders in relatives. Arch Gen Psychiatry, 50(10):781-788. Abstract
Fanous AH, Neale MC, Gardner CO, Webb BT, Straub RE, O'Neill FA, Walsh D, Riley BP, Kendler KS. Significant correlation in linkage signals from genome-wide scans of schizophrenia and schizotypy. Mol Psychiatry. 2007 Oct;12(10):958-65. Abstract
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Related News: GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects
Comment by: Lawrence Kegeles, Dikoma C. Shungu
Submitted 4 April 2012
Posted 5 April 2012
The news story by Allison Curley on our recent paper gives a concise and insightful overview of in-vivo studies of GABA levels in schizophrenia. As the story notes, for those keeping score, studies measuring GABA in schizophrenia are evenly split in that two showed increases, two found decreases, and one reported no change. A major theme running through the thoughtful commentaries by Ongur, Yoshimura, Yoon and Maddock, and McCarley and colleagues is how to understand the variability across studies.
Some regularities can already be found in these and similar studies of the glutamate system. If we confine the scorekeeping to GABA in the prefrontal cortex (PFC), the studies are more uniform: two showed increases (Ongur et al., 2010; Kegeles et al., 2012) and two showed no change (Goto et al., 2009; Tayoshi et al., 2010). If we further limit attention to unmedicated patients, but broaden the review to include the glutamatergic system as well as GABA in the PFC, the studies all agree: glutamine, glutamate-glutamine (Glx), or GABA is increased in the medial PFC (Bartha et al., 1997; Théberge et al., 2002; Théberge et al., 2007; Kegeles et al., 2012), but unchanged in the dorsolateral PFC (Stanley et al., 1996; Ohrmann et al., 2007; Kegeles et al., 2012).
It is encouraging to find patterns where we can, but so far these are limited. We still need (and have begun) to investigate other important brain regions, and it is essential to understand the effects of antipsychotic medication. The commentary by Yoshimura describes the subjects studied by Goto et al. (2009) as medicated and unmedicated, and we wonder if a comparison between those subsamples, as we did in our study, might be informative.
Besides brain region and medication status, the commentaries suggest other patient, treatment, or technical measurement factors contributing to the variability. These include chronicity or duration of illness, medications other than antipsychotics such as benzodiazepines and anticonvulsants, and specifics of MRS methodology. We share these views and encourage any efforts to find systematic impacts of these variables.
Yoon and Maddock raise technical cautions: use of phased-array head coils can limit signal detection in deeper brain regions, and movement artifacts might introduce spurious group differences. As their commentary notes, regions adjacent to the coil elements, such as the occipital lobe (or the dorsolateral PFC) will yield greater signal than deeper structures. In our study, it was the surface region, the dorsolateral PFC, where no group difference was detected, and the slightly deeper medial PFC that showed differences, suggesting adequate sensitivity in the deeper region. Acquisition parameters can be used to offset the coil depth effect. In our study, we enhanced the medial PFC signal by doubling the volume, tending to offset the greater distance from the coil array. Head movement might raise special concerns as a source of artifact in a technique such as MEGA PRESS that relies on subtraction of sequentially acquired spectra, and Yoon and Maddock raise the possibility of resulting over- or underestimation of GABA concentration. Evidence that this may not have occurred in our study is the agreement of our Glx data with prior studies in both medial (Bartha et al., 1997; Théberge et al., 2002; Théberge et al., 2007) and dorsolateral PFC (Stanley et al., 1996; Ohrmann et al., 2007) that did not use MEGA PRESS. Our Glx and GABA measurements that did use MEGA PRESS were correlated and were both elevated in medial PFC, so the agreement with prior methodologies seems to lessen the likelihood of artifacts specific to subtraction methodology. Also, the deeper region (medial PFC) would be expected to undergo less movement than the surface region, yet showed the elevations. Additional evidence that movement artifact may not be a confounder in MEGA PRESS measurements is a recent study by Hasler et al., (2007) in major depression, where a very different pattern of abnormalities was seen in medial PFC (decreased Glx and unchanged GABA). It seems unlikely that patients with depression and schizophrenia would exhibit movement patterns systematically different from controls, yet so different from each other as to have generally opposite impacts on the outcome measures. However, these are all indirect considerations. Systematic characterization of movement effects in MEGA PRESS and other acquisition sequences could add important specific data on potential artifacts, and these issues deserve further study.
Another theme of the commentary is the apparent discrepancy between postmortem markers of GABA function and parenchymal GABA measured in vivo with MRS. There is a clear indication of diminished GABA function associated with fast-spiking, parvalbumin-positive GABA interneurons in the postmortem findings, yet we reported an elevation of parenchymal GABA concentration in vivo in the medial PFC. Ongur’s commentary raises the interesting possibility of abnormally increased storage in synaptic vesicles, while Yoon and Maddock cite evidence from animal studies of equilibrium between vesicular and non-vesicular GABA pools. Possibilities are a disruption of this normal equilibrium in schizophrenia and, alternatively, a compensatory increase in GABA signaling from the non-parvalbumin interneurons. These speculative possibilities raise the questions of detectable postmortem markers of abnormal vesicular function or heightened signaling by the non-fast-spiking interneurons.
Finally, the commentaries offered important observations on the functional role of total tissue GABA levels. Since neurotransmission is only one of several compartments contributing to parenchymal GABA, it is reasonable to wonder whether this MRS measurement has any detectable functional significance at all. Our study found no relation between elevated parenchymal GABA and working memory performance. We did find a relationship to positive symptoms that did not survive multiple comparisons correction, but suggests a focus for future testing. Yoon and Maddock cite several studies documenting functional importance of total GABA (Edden et al., 2009; Sumner et al., 2010; Yoon et al., 2010). McCarley and colleagues note in their commentary that relationships to physiological measures such as gamma oscillations suggest that bulk GABA is functionally meaningful (see also Muthukumaraswamy et al., 2009).
In the end, if we can develop a consistent picture of GABA abnormalities in schizophrenia, the primary motivation for all of these studies is to establish their functional relevance, and to raise the possibility of interventions designed to restore not only normal levels, but also, more importantly, normal function.
Bartha R, Williamson PC, Drost DJ, Malla A, Carr TJ, Cortese L, Canaran G, Rylett RJ, Neufeld RWJ (1997) Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 54:959-65. Abstract
Edden RA, Muthukumaraswamy SD, Freeman TC, Singh KD (2009) Orientation discrimination performance is predicted by GABA concentration and gamma oscillation frequency in human primary visual cortex. J Neurosci 29:15721-6. Abstract
Goto N, Yoshimura R, Moriya J, Kakeda S, Ueda N, Ikenouchi-Sugita A, Umene-Nakano W, Hayashi K, Oonari N, Korogi Y, Nakamura J (2009) Reduction of brain gamma-aminobutyric acid (GABA) concentrations in early-stage schizophrenia patients: 3T Proton MRS study. Schizophr Res 112:192-3. Abstract
Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC (2007) Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 64:193-200. Abstract
Muthukumaraswamy SD, Edden RA, Jones DK, Swettenham JB, Singh KD (2009) Resting GABA concentration predicts peak gamma frequency and fMRI amplitude in response to visual stimulation in humans. Proc Natl Acad Sci U S A 106:8356-61. Abstract
Ohrmann P, Siegmund A, Suslow T, Pedersen A, Spitzberg K, Kersting A, Rothermundt M, Arolt V, Heindel W, Pfleiderer B (2007) Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: a proton magnetic resonance spectroscopy study. J Psychiatr Res 41:625-34. Abstract
Ongur D, Prescot AP, McCarthy J, Cohen BM, Renshaw PF (2010) Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Biol Psychiatry 68:667-70. Abstract
Stanley JA, Williamson PC, Drost DJ, Rylett RJ, Carr TJ, Malla A, Thompson RT (1996) An in vivo proton magnetic resonance spectroscopy study of schizophrenia patients. Schizophr Bull 22:597-609. Abstract
Sumner P, Edden RA, Bompas A, Evans CJ, Singh KD (2010) More GABA, less distraction: a neurochemical predictor of motor decision speed. Nat Neurosci 13:825-7. Abstract
Tayoshi S, Nakataki M, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S, Iga J, Ueno S, Harada M, Ohmori T (2010) GABA concentration in schizophrenia patients and the effects of antipsychotic medication: a proton magnetic resonance spectroscopy study. Schizophr Res 117:83-91. Abstract
Théberge J, Williamson KE, Aoyama N, Drost DJ, Manchanda R, Malla AK, Northcott S, Menon RS, Neufeld RW, Rajakumar N, Pavlosky W, Densmore M, Schaefer B, Williamson PC (2007) Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia. Br J Psychiatry 191:325-34. Abstract
Théberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J, Neufeld RW, Rogers J, Pavlosky W, Schaefer B, Densmore M, Al-Semaan Y, Williamson PC (2002) Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am J Psychiatry 159:1944-6. Abstract
Yoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD, Carter CS (2010) GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci 30:3777-81. Abstract
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