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Assessment of Glutamate Transporter GLAST (EAAT1)-Deficient Mice for Phenotypes Relevant to the Negative and Executive/Cognitive Symptoms of Schizophrenia
Open accessAbstract
Glutamatergic dysfunction is increasingly implicated in the pathophysiology of schizophrenia. Current models postulate that dysfunction of glutamate and its receptors underlie many of the symptoms in this disease. However, the mechanisms involved are not well understood. Although elucidating the role for glutamate transporters in the disease has been limited by the absence of pharmacological tools that selectively target the transporter, we recently showed that glial glutamate and aspartate transporter (GLAST; excitatory amino-acid transporter 1) mutant mice exhibit abnormalities on behavioral measures thought to model the positive symptoms of schizophrenia, some of which were rescued by treatment with either haloperidol or the mGlu2/3 agonist, LY379268 the mGlu2/3 agonist, LY379268. To further determine the role of GLAST in schizophrenia-related behaviors we tested GLAST mutant mice on a series of behavioral paradigms associated with the negative (social withdrawal, anhedonia), sensorimotor gating (prepulse inhibition of startle), and executive/cognitive (discrimination learning, extinction) symptoms of schizophrenia. GLAST knockout (KO) mice showed poor nesting behavior and abnormal sociability, whereas KO and heterozygous (HET) both demonstrated lesser preference for a novel social stimulus compared to wild-type littermate controls. GLAST KO, but not HET, had a significantly reduced acoustic startle response, but no significant deficit in prepulse inhibition of startle. GLAST KO and HET showed normal sucrose preference. In an instrumental visual discrimination task, KO showed impaired learning. By contrast, acquisition and extinction of a simple instrumental response was normal. The mGlu2/3 agonist, LY379268, failed to rescue the discrimination impairment in KO mice. These findings demonstrate that gene deletion of GLAST produces select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia.
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“Alterations in astrocytic glutamate clearance are known to occur in schizophrenia and other psychiatric illnesses, and mice with glutamate/aspartate transporter (GLAST) deletion show phenotypic abnormalities such as mental and behavioral deficits. 90 , 91”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [90]
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Metadata
- Authors
- Karlsson, R.-M., Tanaka, K., Saksida, L. M., Bussey, T. J., Heilig, M., & Holmes, A.
- Affiliations
- National Institutes of Health (US)
- Tokyo Medical and Dental University (JP)
- University of Cambridge (GB)
- Corresponding author
- Karlsson, Rose-Marie
- Venue
- Neuropsychopharmacology
- Published
- 2008-12-10
- Volume
- 34
- Issue
- 6
- Pages
- 1578-1589
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3400972
- OpenAlex
- W2084421163
- Cited by
- 165
- References
- 66
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 9 · 2020: 6 · 2019: 9 · 2018: 11 · 2017: 5 · 2016: 10 · 2015: 12 · 2014: 11 · 2013: 17 · 2012: 16
- FWCI
- 7.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Johns Hopkins University
- Novartis Foundation
- Tokyo Biochemical Research Foundation
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Research Foundation for Opto-Science and Technology
- National Institutes of Health
- Japan Society for the Promotion of Science (20022013, 18053006)
- National Institute on Alcohol Abuse and Alcoholism (ZIAAA000411)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- GLAST, glutamate transporters, schizophrenia, negative symptoms, cognitive symptoms, prepulse inhibition, acoustic startle response, social withdrawal, anhedonia, visual discrimination learning, extinction learning, LY379268, haloperidol, knockout mice
- MeSH terms
- Amino Acids, Animals, Cognition, Cognition Disorders, Disease Models, Animal, Female, Food Preferences, Learning, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Phenotype, Schizophrenia, Social Behavior Disorders, Reflex, Startle, Sucrose, Receptors, Metabotropic Glutamate, Bridged Bicyclo Compounds, Heterocyclic, Excitatory Amino Acid Transporter 1, Mice
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