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Interneuron Pathology Hints at Schizophrenia Subtype

3 October 2012. In schizophrenia, the cortex is short of transcripts for a protein critical for interneuron development, according to a postmortem study published online 13 September in American Journal of Psychiatry. Led by David Lewis of University of Pittsburgh, the study found that mRNA levels for Lhx6, a transcriptional factor involved in interneuron migration, differentiation, and maturation, was lower than those in controls. In combination with transcript deficits for other interneuron markers, the Lhx6 decreases distinguished a subset of schizophrenia cases. This suggests that some, but not all, with the disorder may have accentuated deficits in inhibitory signaling.

The study addresses the origin of disturbances in gamma-aminobutyric acid (GABA) signaling found in schizophrenia in postmortem studies (see SRF related news story). In prefrontal cortex, Lewis and others have consistently found reduced levels of GAD67, an enzyme that makes the inhibitory GABA neurotransmitter. The GAD67 deficits are localized to parvalbumin- and somatostatin-containing interneurons, just two of many different interneuron types in the cortex. Because parvalbumin-containing interneurons have a synchronizing effect on cortical circuits, and are thought to contribute to gamma oscillations and associated working memory, they make an appealing locus of pathology for schizophrenia (Lewis et al., 2005). But why are these, and their somatostatin-containing brethren singled out for a GAD67 deficit in schizophrenia?

To answer this, the researchers looked to development, as reflected in the levels of Lhx6 and Sox6. Both genes are transcription factors involved in directing would-be interneurons to their places in the cortex, inducing them to assume their parvalbumin- or somatostatin-containing identities, and regulating their GABA production. Despite their key roles in development, Lhx6 and Sox6 remain highly expressed in adulthood, and any differences found in adult brain tissue in schizophrenia could reflect a vestige of derailed development.

Look at Lhx6
First authors David Volk and Takurou Matsubara studied postmortem brain tissue from prefrontal cortex obtained from 42 adults with schizophrenia and 42 age- and sex-matched controls. After extracting mRNA from these samples, they measured the amounts of parvalbumin, somatostatin, calretinin, Lhx6, and Sox6 transcripts with quantitative PCR. As previously reported, this revealed lower levels of parvalbumin (the difference amounting to 22 percent of control levels) and somatostatin (-36 percent) in the schizophrenia group as a whole compared to controls. An increase was also found in schizophrenia for calretinin (+9 percent), a marker of a different subtype of interneurons, ones that originate in a different area from the parvalbumin and somatostatin interneurons,.

Looking at the transcription factors, Lhx6, but not Sox6, was lower in schizophrenia compared to controls (-10 percent for Lhx6). The researchers further examined this finding with in situ hybridization in order to localize Lhx6 in the cortex of 22 subject pairs, for which they had the tissue. Again this turned up a similarly diminished level of Lhx6, particularly in layers 3, 5, and 6, which contain parvalbumin- and somatostatin-containing interneurons. The density of neurons positively labeled with their Lhx6 probe was decreased, as was the amount of labeling per cell, indicating both fewer Lhx6-expressing interneurons, and waning Lhx6 expression in those with detectable expression.

Clustering cases
Noting that deficits in parvalbumin and somatostatin were not shared by every schizophrenia sample in their group, the researchers explored whether a certain pattern of transcript deficits distinguished a subset of their samples. Using cluster analysis to group all brains—schizophrenia and controls alike—according to the similarity in their transcript levels of GAD67, parvalbumin, somatostatin, and Lhx6, the researchers found two clusters: one containing a mixture of schizophrenia and control samples (n = 61), and one dominated by schizophrenia samples (n = 23), with only 3 controls. The 20 schizophrenia samples in the latter cluster had significantly lower mRNA levels of Lhx6, parvalbumin, somatostatin, and GAD67 compared to the schizophrenia samples not in this cluster, and to all controls; no differences emerged for calretinin and Sox6. Together the results suggest that a subset of schizophrenia cases are marked by a dearth of GABA-related transcripts, particularly those associated with Lhx6.

These transcript deficits were not explained by medication history or illness severity. Consistent with this, the researchers found that treating monkeys with the antipsychotics haloperidol or olanzapine did not curtail Lhx6 expression either, similar to their previous results for parvalbumin, somatostatin and GAD67. This, combined with the fact that Sox6 transcripts were unchanged, argues against an effect of the illness on transcriptional regulators in adulthood. This then suggests that the Lhx6 deficit observed in these adult brains may be a long-lasting mark of faulty development. Future studies will have to tease out when and how it arises, and whether it is related to the other expression deficits. If further studies uphold the idea of a subset of schizophrenia cases distinguished by GABA-related dysfunction, then this could help clear up discrepancies in the GABA-in-schizophrenia literature (see SRF related news story), and potentially predict better clinical response to drugs that boost GABA signaling.—Michele Solis.

Volk DW, Matsubara T, Li S, Sengupta EJ, Georgiev D, Minabe Y, Sampson A, Hashimoto T, Lewis DA. Deficits in Transcriptional Regulators of Cortical Parvalbumin Neurons in Schizophrenia. Am J Psychiatry. 2012 Sep 13. Abstract

Comments on News and Primary Papers

Primary Papers: Deficits in transcriptional regulators of cortical parvalbumin neurons in schizophrenia.

Comment by:  Cynthia Shannon Weickert, SRF Advisor
Submitted 21 September 2012
Posted 23 September 2012
  I recommend this paper

This is an interesting paper that takes us another important step forward in understanding the molecular nature of cortical interneuron dysfunction in schizophrenia. Nice job to David and the team!

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Comments on Related News

Related News: Genetics, Expression Profiling Support GABA Deficits in Schizophrenia

Comment 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.

View all comments by Karoly Mirnics

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 neurotransmission.

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.

View all comments by Dost Ongur

Related News: GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects

Comment by:  Jong H. YoonRichard 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 McCarleyMargaret NiznikiewiczMartina M. VoglmaierKevin Spencer (Disclosure), Nick BoloAlexander P. LinYouji HiranoElisabetta del ReIsrael MolinaVicky LiaoSai 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 KegelesDikoma 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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Related News: Brain Anatomy Revealed With CLARITY

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 10 April 2013
Posted 10 April 2013

The Deisseroth lab has done it again! This is an amazing technical advance that can revolutionize the way we do histology and microcircuitry studies. Also, this will be very relevant for human postmortem research, as it will allow better 3-D understanding of the local connectivity. The pictures are very impressive, although I have some potential concerns with the antibody penetration, at least in some cases. In addition, it is noteworthy that this technology will require additional, non-trivial investment in equipment, and it might be (at least initially) best suited for core facilities.

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Related News: Brain Anatomy Revealed With CLARITY

Comment by:  Philip Seeman (Disclosure)
Submitted 11 April 2013
Posted 12 April 2013

Ramón y Cajal is alive and well, but renamed Karl Deisseroth.

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Related News: ErbB4 Deletion Models Aspects of Schizophrenia

Comment by:  Beatriz RicoOscar Marin
Submitted 30 October 2013
Posted 5 November 2013

We would like to provide an answer to the question raised by Andrés Buonanno: “If the knockouts have more γ power, why do they perform less well on the Y maze?” As explained in the manuscript, the abnormal increase in γ power observed in conditional ErbB4 mutants would not necessarily lead to better performance, because interneurons are not pacing pyramidal cells at the proper/normal rhythm. In addition, local hypersynchrony seems to affect long-range functional connectivity: We showed a prominent decoupling between the hippocampus and prefrontal cortex. The increase in excitability and synchrony, and the decoupling between the hippocampus and prefrontal cortex, are likely the cause of the behavioral deficits in cognitive function.

In line with this, we respectfully disagree with Buonanno's next comment that “these data are also at odds with what has been observed in schizophrenia.” Indeed, as we mentioned in the manuscript, recent studies indicate that medication-naive, first-episode, and chronic patients with schizophrenia show elevated γ-band power in resting state. Baseline increases in γ oscillations are consistent with increases in the excitatory/inhibitory ratio of cortical neurons. Thus, cortical rhythm abnormalities in schizophrenia seem to include both abnormal increases in baseline power—as we observed in conditional ErbB4 mutants—as well as deficits in task-related oscillations (Uhlhaas and Singer, 2012).


Uhlhaas PJ, and Singer W. (2012). Neuronal dynamics and neuropsychiatric disorders: toward a translational paradigm for dysfunctional large-scale net- works. Neuron 75, 963–980. Abstract

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