Hyperfunction of Dopaminergic and Serotonergic Neuronal Systems in Mice Lacking the NMDA Receptor epsilon 1 Subunit

• Published in: The Journal of neuroscience 2001-01, Vol.21 (2), p.750-757
• Main Authors: Miyamoto, Yoshiaki, Yamada, Kiyofumi, Noda, Yukihiro, Mori, Hisashi, Mishina, Masayoshi, Nabeshima, Toshitaka
• Format: Article
• Language: English
• ISSN: 0270-6474
• DOI: 10.1523/JNEUROSCI.21-02-00750.2001

NMDA receptors, an ionotropic subtype of glutamate receptors (GluRs) forming high Ca super(2+)-permeable cation channels, are composed by assembly of the GluR zeta subunit (NR1) with any one of four GluR epsilon subunits (GluR epsilon 1-4; NR2A-D). In the present study, we investigated neuronal functions in mice lacking the GluR epsilon 1 subunit. GluR epsilon 1 mutant mice exhibited a malfunction of NMDA receptors, as evidenced by alterations of [ super(3)H]MK-801 binding as well as super(45)Ca super(2+) uptake through the NMDA receptors. A postmortem brain analysis revealed that both dopamine and serotonin metabolism were increased in the frontal cortex and striatum of GluR epsilon 1 mutant mice. The NMDA-stimulated [ super(3)H]dopamine release from the striatum was increased, whereas [ super(3)H]GABA release was markedly diminished in GluR epsilon 1 mutant mice. When (+)bicuculline, a GABA sub(A) receptor antagonist, was added to the superfusion buffer, NMDA-stimulated [ super(3)H]dopamine release was significantly increased in wild-type, but not in the mutant mice. GluR epsilon 1 mutant mice exhibited an increased spontaneous locomotor activity in a novel environment and an impairment of latent learning in a water-finding task. Hyperlocomotion in GluR epsilon 1 mutant mice was attenuated by treatment with haloperidol and risperidone, both of which are clinically used antipsychotic drugs, at doses that had no effect in wild-type mice. These findings provide evidence that NMDA receptors are involved in the regulation of behavior through the modulation of dopaminergic and serotonergic neuronal systems. In addition, our findings suggest that GluR epsilon 1 mutant mice are useful as an animal model of psychosis that is associated with NMDA receptor malfunction and hyperfunction of dopaminergic and serotonergic neuronal systems.