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GABA Is Up in Prefrontal Cortex of Schizophrenia Subjects

11 January 2012. The quest to clarify the state of GABAergic neurotransmission in schizophrenia continues. In the first study that looks at patients not receiving antipsychotic drugs, Lawrence Kegeles of Columbia University and Dikoma Shungu of Weill Cornell Medical College, both in New York City, and their colleagues found a 30 percent increase in medial prefrontal cortex GABA levels in unmedicated subjects compared to control subjects, but no change in subjects being treated with antipsychotics.

Interestingly, the proton magnetic resonance spectroscopy (1H MRS) study, published online January 2 in the Archives of General Psychiatry, found no change in levels of the inhibitory neurotransmitter in the dorsolateral prefrontal cortex of either unmedicated or medicated subjects.

The inhibitor-in-chief in schizophrenia
Dysfunction of the GABA system in schizophrenia has a great deal of support from postmortem work (see SRF related news story), and includes alterations in several pre- and post-synaptic markers of inhibitory neurotransmission thought to be prominent in parvalbumin neurons (Akbarian et al., 1995; Hashimoto et al., 2003; Fung et al., 2010). Taken together, these studies strongly suggest a reduction in GABA levels in schizophrenia, though they lack the proof that a direct measurement of GABA levels could provide.

Beginning in 2009, several studies using 1H MRS have aimed to provide that proof, with conflicting results. One study reported a decrease in GABA levels in the basal ganglia, but not in the frontal or parieto-occipital lobes (Goto et al., 2009), while another found no change in the basal ganglia or anterior cingulate cortex (Tayoshi et al., 2010). In contrast, Ongür and colleagues have reported increased GABA in the anterior cingulate and parieto-occipital cortices (Ongür et al., 2010), while Yoon et al. found lower GABA levels in the visual cortex (Yoon et al., 2010).

Washing out the confounder
One potential confound of these studies is the use of cohorts in which most or all of the schizophrenia subjects have received antipsychotics, making assessments of the role of medication difficult at best. However, in the present 1H MRS study, Kegeles and colleagues assessed GABA levels in 32 schizophrenia subjects, half unmedicated, and 22 healthy controls. They observed increased GABA levels in the medial PFC in unmedicated schizophrenia subjects, but not those who were treated with antipsychotics. In contrast, there was no difference between diagnostic groups in dorsolateral PFC GABA levels.

According to the authors, one potential reconciliation between the current findings and the large body of postmortem data suggestive of reduced GABA transmission is that elevated GABA levels may reflect a compensatory increase in signaling from the non-parvalbumin classes of interneurons. These surprising results may also indicate a “normalization” of elevated GABA levels with antipsychotic treatment, consistent with evidence in rodents that dopamine D2 receptor antagonists can lower GABA levels (Bourdelais and Deutch, 1994). As Kegeles and colleagues note in the discussion section, future studies using a within-subject design may help to better establish the effect of antipsychotics.

The levels of glutamate-glutamine, a mixture thought to mainly be glutamate (Kaiser et al., 2005), in the same subjects exhibited a similar pattern: a 30 percent increase in the medial PFC of unmedicated subjects (but no changes in the dorsolateral PFC or in medicated subjects in either region). Similar to the GABA 1H MRS literature, reports of glutamate-glutamine levels in schizophrenia are mixed, although the present data are in agreement with previous reports in the medial PFC (Bartha et al., 1997) and other brain regions (Théberge et al., 2002; Théberge et al., 2007). In addition, elevated glutamate-glutamine levels are consistent with the hypothesis that pyramidal cell disinhibition results from N-methyl-D-aspartate (NMDA) receptor hypofunction on parvalbumin interneurons in schizophrenia (Lisman et al., 2008).

For those keeping score, studies measuring GABA levels in schizophrenia are now split evenly—two studies have found an increase, two have shown a decrease, and one found no change. An important limitation of all 1H MRS measures is that spectroscopic studies assess total tissue GABA levels, not those associated with synapses. Thus, the relationship between MRS-measured GABA levels and altered GABAergic transmission in schizophrenia remains unclear.—Allison A. Curley*

*Disclosure: Allison Curley is a Postdoctoral Associate in the laboratory of David Lewis at the University of Pittsburgh, where she studies the role of altered markers of GABA neurotransmission in schizophrenia.

Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X, Gil R, Slifstein M, Abi-Dargham A, Lisanby SH, Shungu DC. Elevated Prefrontal Cortex ?-Aminobutyric Acid and Glutamate-Glutamine Levels in Schizophrenia Measured In Vivo With Proton Magnetic Resonance Spectroscopy. Arch Gen Psychiatry. 2012 Jan 2. Abstract

Comments on News and Primary Papers
Comment by:  Dost Ongur
Submitted 19 January 2012 Posted 19 January 2012

This news story by Allison Curley cogently and succinctly...  Read more

View all comments by Dost Ongur

Primary Papers: Elevated prefrontal cortex ?-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy.

Comment by:  Reiji Yoshimura
Submitted 23 January 2012 Posted 25 January 2012
  I recommend this paper

The GABA theory of schizophrenia is very attractive. I...  Read more

View all comments by Reiji Yoshimura

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...  Read more

View all comments by Jong H. Yoon
View all comments by Richard J. Maddock

Comment by:  Robert McCarleyMargaret NiznikiewiczMartina M. VoglmaierKevin Spencer (Disclosure)
Nick Bolo
Alexander P. LinYouji Hirano
Elisabetta del Re
Israel MolinaVicky 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...  Read more

View all comments by Robert McCarley
View all comments by Margaret Niznikiewicz
View all comments by Martina M. Voglmaier
View all comments by Kevin Spencer
View all comments by Nick Bolo
View all comments by Alexander P. Lin
View all comments by Youji Hirano
View all comments by Elisabetta del Re
View all comments by Israel Molina
View all comments by Vicky Liao
View all comments by Sai Merugumala

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...  Read more

View all comments by Lawrence Kegeles
View all comments by Dikoma C. Shungu
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