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.
BACKGROUND
Recent data suggest that excessive glutamatergic signaling in the prefrontal cortex may contribute to the pathophysiology of schizophrenia and that promoting presynaptic glutamate modulation via group II metabotropic glutamate 2/3 (mGlu2/3) receptor activation can exert antipsychotic efficacy. The glial glutamate and aspartate transporter (GLAST) (excitatory amino acid transporter 1 [EAAT1]) regulates extracellular glutamate levels via uptake into glia, but the consequences of GLAST dysfunction for schizophrenia are largely unknown.


METHODS
We examined GLAST knockout mice (KO) for behaviors thought to model positive symptoms in schizophrenia (locomotor hyperactivity to novelty, exaggerated locomotor response to N-methyl-d-aspartate receptor [NMDAR] antagonism) and the ability of haloperidol and the mGlu2/3 agonist LY379268 to normalize novelty-induced hyperactivity.


RESULTS
Glial glutamate and aspartate transporter KO consistently showed locomotor hyperactivity to a novel but not familiar environment, relative to wild-type (WT) mice. The locomotor hyperactivity-inducing effects of the NMDAR antagonist MK-801 was exaggerated in GLAST KO relative to WT. Treatment with haloperidol or LY379268 normalized novelty-induced locomotor hyperactivity in GLAST KO.


CONCLUSIONS
Schizophrenia-related abnormalities in GLAST KO raise the possibility that loss of GLAST-mediated glutamate clearance could be a pathophysiological risk factor for the disease. Our findings provide novel support for the hypothesis that glutamate dysregulation contributes to the pathophysiology of schizophrenia and for the antipsychotic potential of mGlu2/3 agonists.
Karlsson
Rose-Marie
RM
Laboratory for Clinical and Translational Studies, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, Maryland 20892, USA. karlssonr@mail.nih.gov
Tanaka
Kohichi
K
Heilig
Markus
M
Holmes
Andrew
A
D000596:Amino Acids / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000172:deficiency*; D005106:Exploratory Behavior / Q000187:drug effects; D006220:Haloperidol / Q000627:therapeutic use*; D006948:Hyperkinesis / Q000235:genetics*; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists
D000596:Amino Acids; D018726:Anti-Dyskinesia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; D027341:Excitatory Amino Acid Transporter 1; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C493393:Slc1a3 protein, mouse; D016291:Dizocilpine Maleate; D006220:Haloperidol