Glutamate: Too much of a good thing in schizophrenia?
Is schizophrenia a disorder of glutamate hyperactivity or hypoactivity? While the predominant hypothesis for many years was that schizophrenia was a glutamate deficit disorder, there is growing evidence of glutamate hyperactivity as well.
The study by Karlsson et al., appearing in the November 1st issue of Biological Psychiatry, reinforces this point with new data about the impact of deleting the gene for the glutamate transporter EAAT1. EAAT1, implicated in schizophrenia, plays a critical role in inactivating glutamate by removing it from the synaptic and extracellular spaces. The authors demonstrate that these “knockout” animals show increased responses to the NMDA glutamate receptor antagonist, MK-801.
This drug causes the release of more glutamate into the synapse in the frontal cortex. This effect of MK-801 is reduced by a group II metabotropic glutamate receptor agonist, which reduces glutamate release.
Dr. Andrew Holmes, corresponding author, further discusses their findings, “Our study adds a new twist to [glutamate] research by showing that genetically disrupting a major regulator of glutamate’s ability to communicate between nerve cells produces certain ‘schizophrenia-like’ features in mice and, moreover, that these abnormalities can be corrected by a highly promising new class of glutamate-targeting antipsychotic treatments.” In fact, this class of drugs has already shown some preliminary efficacy in its ability to treat individuals suffering from schizophrenia.
John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, comments: “The NMDA receptor antagonist model and the EAAT1 knockout animal push us to take a fresh look at the obstacles to treating cognitive impairments associated with schizophrenia, in other words, optimizing their cortical network function. This new look can lead us to drugs that would have been completely surprising as recently as 10 years ago, such as the group II metabotropic glutamate receptor agonists.”
Dr. Holmes does note that further research is warranted, stating, “What is now needed is more research to get a better handle on how disrupting this gene affects the brain’s neural wiring and molecular signaling pathways to produce the symptoms of schizophrenia.” This finding could ultimately help scientists develop new or improved treatments for this schizophrenia.
Notes to Editors:
The article is “Loss of Glial Glutamate and Aspartate Transporter (Excitatory Amino Acid Transporter 1) Causes Locomotor Hyperactivity and Exaggerated Responses to Psychotomimetics: Rescue by Haloperidol and Metabotropic Glutamate 2/3 Agonist” by Rose-Marie Karlsson, Kohichi Tanaka, Markus Heilig, and Andrew Holmes. Drs. Karlsson and Heilig are affiliated with the Laboratory for Clinical and Translational Studies, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, Maryland. Dr. Holmes is from the Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, Maryland. Dr. Tanaka is affiliated with the Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University Bunkyo-ku, Tokyo, Japan. The article appears in Biological Psychiatry, Volume 64, Issue 9 (November 1, 2008), published by Elsevier.
About Biological Psychiatry
This international rapid-publication journal is the official journal of the Society of Biological Psychiatry. It covers a broad range of topics in psychiatric neuroscience and therapeutics. Both basic and clinical contributions are encouraged from all disciplines and research areas relevant to the pathophysiology and treatment of major neuropsychiatric disorders. Full-length and Brief Reports of novel results, Commentaries, Case Studies of unusual significance, and Correspondence and Comments judged to be of high impact to the field are published, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Concise Reviews and Editorials that focus on topics of current research and interest are also published rapidly.
Biological Psychiatry is ranked 4th out of the 95 Psychiatry titles and 16th out of 199 Neurosciences titles on the 2006 ISI Journal Citations Reports® published by Thomson Scientific.
Contact: Jayne Dawkins
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