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.

Abstract

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.

• Authors: Rose-Marie Karlsson, Kohichi Tanaka, Markus Heilig, Andrew Holmes
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 64 Issue 9 Pg. 810-4 (Nov 01 2008) ISSN: 1873-2402 [Electronic] United States
• PMID: 18550032 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Anti-Dyskinesia Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Excitatory Amino Acid Antagonists
• Excitatory Amino Acid Transporter 1
• LY 379268
• Receptors, Metabotropic Glutamate
• Slc1a3 protein, mouse
• Dizocilpine Maleate
• Haloperidol

Topics

• Amino Acids (therapeutic use)
• Analysis of Variance
• Animals
• Anti-Dyskinesia Agents (therapeutic use)
• Behavior, Animal (drug effects)
• Bridged Bicyclo Compounds, Heterocyclic (therapeutic use)
• Dizocilpine Maleate (pharmacology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Excitatory Amino Acid Transporter 1 (deficiency)
• Exploratory Behavior (drug effects)
• Haloperidol (therapeutic use)
• Hyperkinesis (genetics)
• Locomotion (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, Metabotropic Glutamate (agonists)