Schizophrenia Research Forum - A Catalyst for Creative Thinking

Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, Montrose D. Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry. 2008 Dec ; 165(12):1585-93. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Robert McCarley
Submitted 7 November 2008
Posted 7 November 2008

This paper is further evidence of an important and laudable new trend in schizophrenia psychopharmacology: namely the development and test of compounds on the basis of their relationship to circuit abnormalities, evidence derived from postmortem, genetic, and animal model studies. The authors based their choice of MK-0777 for test in schizophrenia on evidence for decreased cortical GABA neurotransmission onto pyramidal neurons at receptors having the α2 subunit, and other evidence pointing to the GABA-pyramidal neuron interaction as important in cognition and in generation of γ band oscillations. In this add-on, double-blind placebo study, the Ns were underpowered and more subjects need to be studied to be certain about clinical effects. However, one test, the Preparing to Overcome Prepotency Test (POP), had significant improvements in response latency and showed concomitant improvement in increased frontal γ band activity induced during the task, although not meeting the criterion for statistical significance. POP requires subjects either to “go with the flow” (indicated by a green light) and respond in the same direction as an arrow, or when cued by a red light to “go upstream” and point in the opposite direction, a test previously used in the Cho et al. 2006 PNAS paper and found to be accompanied by increased induced γ band oscillations.

γ band activity has justifiably attracted considerable attention, since there is mounting evidence of its relevance to human cognition as well as to basic neuroscience studies of neuronal assembly communication. Its important basis in the GABA cortical neuronal interaction with pyramidal cells makes it especially fascinating in schizophrenia. However, an important caution light was recently flashed by Yuval-Greenberg et al. in an article in Neuron (2008) in which they presented strong evidence that apparent increases or decreases in the “induced γ band oscillations” (those not temporally linked to a response or stimulus) could be the result of the eye muscle activation associated with small saccadic eye movements, “a saccadic spike potential” that could be confused with γ band oscillations. The Yuval-Greenberg article appeared too late for the authors to discuss in the present paper, but its implications for future work using induced γ are important. For studies of induced γ, we all will have to begin using eye movement measures sensitive to mini-saccades. Those of us who measure γ phase-locked to measureable events, such as sensory stimuli or responses, appear to be off the hook since we condition on known events, unlike conditions where induced γ is measured.


Cho RY, Konecky RO, Carter CS. Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19878-83. Abstract

Yuval-Greenberg S, Tomer O, Keren AS, Nelken I, Deouell LY. Transient induced gamma-band response in EEG as a manifestation of miniature saccades. Neuron. 2008 May 8;58(3):429-41. Abstract

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