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In the Loop: Schizophrenia and Bipolar Disorder Show Unique GABA Signatures

29 December 2008. A new study concludes that schizophrenia and bipolar disorder show distinct patterns of GABA-related gene expression in specific layers and sectors along the trisynaptic pathway of the hippocampus. Conducted by Francine Benes and her colleagues at McLean Hospital in Belmont, Massachusetts, and Harvard Medical School, it appeared in the PNAS Early Edition released on December 22.

Prior research ties each of these conditions to disturbed GABAergic functioning within corticolimbic areas of the brain (see Wassef et al., 2003; Akbarian and Huang, 2006; Benes and Berretta, 2001), including the prefrontal cortex and the hippocampus. In both schizophrenia and bipolar disorder, evidence points to abnormally low expression of GAD67, an isoform of glutamate decarboxylase, an enzyme that helps convert glutamate into GABA.

Last year, in a PNAS paper, Benes and associates reported that the stratum oriens of sectors CA2 and CA3 of the hippocampus show markedly decreased GAD67 expression in schizophrenia and bipolar disorder, although the underlying mechanisms depended on the diagnosis (see SRF related news story as well as a summary of Benes's talk at the 2007 Society for Neuroscience symposium on integrating neurotransmitter theories in schizophrenia). These sectors receive inputs from the trisynaptic pathway, a circuit within the hippocampus that plays a role in learning and memory, particularly as they relate to emotional states. Starting at the entorhinal cortex, this loop relays excitatory inputs to the dentate gyrus, and subsequently to sectors CA3/2 and then CA1.

Different pictures in different places
The newer study focused on the regulation of gene expression in GABAergic interneurons along the trisynaptic circuit. Benes and colleagues compared postmortem tissue from three matched groups of seven: subjects with schizophrenia, those with bipolar disorder, and normal control subjects. Using laser microdissection, the researchers sampled tissue from three layers of the hippocampus: the stratum oriens, the stratum radiatum, and the stratum pyramidale. GenMAPP algorithms identified clusters of genes at each site that serve similar functions.

As in their earlier study, the researchers found striking changes in the stratum oriens of sectors CA3/2. In schizophrenia, this locus showed increased expression of genes associated with potassium and voltage-gated ion channels. Bipolar disorder showed the opposite pattern, with downregulation of such genes, even as it echoed schizophrenia’s low expression of GAD67. Benes tells SRF that the GABA cells in this layer and sector are thought to generate oscillatory wave patterns that reflect the functional integration of the hippocampal circuit.

Following the pathway to CA1, Benes and colleagues again found reduced GAD67 expression in the stratum oriens in schizophrenia. In contrast, CA1 GABA cells from subjects with bipolar disease seemed to be working normally, although several metabolic and signaling pathways that enable cells to function appeared to be upregulated.

“What we were astonished to see was the degree to which the regulatory mechanisms within GABA cells at different points along the trisynaptic pathway are fundamentally different even within schizophrenia itself, and the same is true of bipolar disorder,” Benes says. Each GABA cell population receives different inputs from outside and within the hippocampus, Benes noted, and she suggests that these fiber systems probably contribute to the complex expression patterns described in this study. Given the complexity of it all, she sees no easy answers or quick fixes on the horizon. Looking at the upside, however, she believes that the work needed to learn how key cell groups function within the specific circuits involved in these disorders will yield more precisely honed molecular therapies.—Victoria L. Wilcox.

Benes FM, Lim B, Matzilevich D, Subburaju S, Walsh J. Circuitry-based gene expression profiles in GABA cells of the trisynaptic pathway in schizophrenics versus bipolars. PNAS Early Edition. 2008, Dec 22. Abstract

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.

View all comments by Schahram Akbarian