Schizophrenia Research Forum - A Catalyst for Creative Thinking

Small Brain Changes Have Big Impact

October 16, 2013. By manipulating a gene suspected to be involved in schizophrenia, researchers were able to make small changes in brain cells, with big consequences. As reported in a new study published September 18, 2013, in Neuron, even small changes to the connections between brain cells produce large changes to the overall circuitry of the brain, as well as in behaviors that may be relevant to the symptoms of schizophrenia.

Oscar Marín and Beatriz Rico of CSIC-University Miguel Hernández in Alicante, Spain, and their colleagues genetically engineered a group of mice to have lower levels of the brain molecule ErbB4, which has previously been linked to schizophrenia. The method is so precise that they were able to alter the ErbB4 levels just in a particular kind of brain cell, the interneuron. There is good evidence that these cells are malfunctioning in the illness and that they may be responsible for the thinking and memory deficits that are so detrimental to a patient’s quality of life.

Turning off the ErbB4 gene in the interneurons resulted in relatively small changes in the connections between neurons, but much greater alterations in how they interact to produce thought and behavior. Although the symptoms of schizophrenia cannot be truly modeled in a mouse model such as this, and some alterations that are present are different from findings in the illness, this study points to a connection among the ErbB4 molecule, problems with interneuron signaling, and schizophrenia. (For more details, see the related news story.)—Allison A. Curley.

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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).

References:

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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