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Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia.

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.

SUBMITTER: Karlsson RM

PROVIDER: S-EPMC3400972 | biostudies-other | 2009 May

REPOSITORIES: biostudies-other

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Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia.

Karlsson Rose-Marie RM Tanaka Kohichi K Saksida Lisa M LM Bussey Timothy J TJ Heilig Markus M Holmes Andrew A

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20081210 6

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 tran ...[more]

PMID: 19078949

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Project description:The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (r(s)=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (r(s)=0.74, p=0.046). In addition, baseline pregnenolone (r(s)=-0.76, p=0.037), pregnenolone sulfate (r(s)=-0.83, p=0.015), and allopregnanolone levels (r(s)=-0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (r(s)=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

Dataset Information

Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia.

Publications

Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia.

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