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Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia |
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| Authors: | Lisman John E Coyle Joseph T Green Robert W Javitt Daniel C Benes Francine M Heckers Stephan Grace Anthony A |
| Affiliation: | 1Department of Biology, Brandeis University, 415 South Street, Waltham, MA 02454, USA 2Department of Psychiatry, McLean Hospital–Harvard Medical School, 115 Mill Street, Administration Building, Belmont, MA 02478-9110, USA 3Department of Psychology, University of Texas Southwestern and Veterans Affairs Medical Center, 4500 South Lancaster Road, 116A, Dallas, TX 75216, USA 4Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute, 140 Old Orangeburg Road, Room S235, Orangeburg, NY 10962, USA 5Program in Structural and Molecular Neuroscience, McLean Hospital, Mailman Research Center, 115 Mill Street, Belmont, MA 02478, USA 6Department of Psychiatry, Vanderbilt University, 1601 23rd Avenue South, Room 3060, Nashville, TN 37212, USA 7Departments of Neuroscience, Psychiatry and Psychology, Center for Neuroscience, A210 Langley Hall, University of Pittsburgh, Pittsburgh, PA 15217, USA |
| Abstract: | Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia. |
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