The GABA-glutamate connection in schizophrenia: which is the proximate cause?
Schizophrenia is a chronic, disabling psychiatric disorder that genetic studies have shown to be highly heritable. Although the dopamine hypothesis has dominated the thinking about the cause of schizophrenia for 40 years, post-mortem and genetic studies have provided little support for it. Rather, post-mortem studies point to hypofunction of subsets of GABAergic interneurons in the prefrontal cortex and the hippocampus. Furthermore, clinical pharmacologic, post-mortem and genetic studies have provided compelling evidence of hypofunction of a subpopulation of NMDA receptors in schizophrenia. In support of this inference, agents that directly or indirectly activate the glycine modulatory site on the NMDA receptor (the Glycine B receptor) reduce symptoms in chronic schizophrenia, especially negative symptoms and cognitive impairments. Electrophysiologic and pharmacologic studies suggest that the vulnerable NMDA receptors in schizophrenia may be concentrated on cortico-limbic GABAergic interneurons, thereby linking these two neuropathologic features of the disorder.[1]References
- The GABA-glutamate connection in schizophrenia: which is the proximate cause? Coyle, J.T. Biochem. Pharmacol. (2004) [Pubmed]
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