1. ¹Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
2. ²Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
3. ³Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
4. ⁴Department of Experimental Psychology, University of Cambridge, Cambridge, UK
5. ⁵The Medical Research Council and Wellcome Trust Behavioral and Clinical Neuroscience Institute, Cambridge, UK
6. ⁶Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Rockville, MD, USA

Correspondence: R-M Karlsson, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, 10-Center Drive, 10 Room 1E-5330, Bethesda, MD 20892, USA. Tel: +1 301 443 2674; Fax: +1 301 480 1952; E-mail: karlssonr@mail.nih.gov

Received 2 October 2008; Revised 5 November 2008; Accepted 5 November 2008; Published online 10 December 2008.

Abstract

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.