Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor ε1 subunit

Yoshiaki Miyamoto, Kiyofumi Yamada, Yukihiro Noda, Hisashi Mori, Masayoshi Mishina, Toshitaka Nabeshima

Research output: Contribution to journalArticle

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Abstract

NMDA receptors, an ionotropic subtype of glutamate receptors (GluRs) forming high Ca2+-permeable cation channels, are composed by assembly of the GluRζ subunit (NR1) with any one of four GluRε subunits (GluRε1-4; NR2A-D). In the present study, we investigated neuronal functions in mice lacking the GluRε1 subunit. GluRε1 mutant mice exhibited a malfunction of NMDA receptors, as evidenced by alterations of [3H]MK-801 binding as well as 45Ca2+ 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 GluRε1 mutant mice. The NMDA-stimulated [3H]dopamine release from the striatum was increased, whereas [3H]GABA release was markedly diminished in GluRε1 mutant mice. When (+)bicuculline, a GABAA receptor antagonist, was added to the superfusion buffer, NMDA-stimulated [3H]dopamine release was significantly increased in wild-type, but not in the mutant mice. GluRε1 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 GluRε1 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 GluRε1 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.

Original languageEnglish
Pages (from-to)750-757
Number of pages8
JournalJournal of Neuroscience
Volume21
Issue number2
Publication statusPublished - 15-01-2001
Externally publishedYes

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N-Methyl-D-Aspartate Receptors
Dopamine
N-Methylaspartate
Ionotropic Glutamate Receptors
GABA-A Receptor Antagonists
Risperidone
Dizocilpine Maleate
Bicuculline
Frontal Lobe
Haloperidol
Locomotion
Psychotic Disorders
gamma-Aminobutyric Acid
Antipsychotic Agents
Cations
Serotonin
Buffers
Animal Models
Learning
Water

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Miyamoto, Yoshiaki ; Yamada, Kiyofumi ; Noda, Yukihiro ; Mori, Hisashi ; Mishina, Masayoshi ; Nabeshima, Toshitaka. / Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor ε1 subunit. In: Journal of Neuroscience. 2001 ; Vol. 21, No. 2. pp. 750-757.
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Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor ε1 subunit. / Miyamoto, Yoshiaki; Yamada, Kiyofumi; Noda, Yukihiro; Mori, Hisashi; Mishina, Masayoshi; Nabeshima, Toshitaka.

In: Journal of Neuroscience, Vol. 21, No. 2, 15.01.2001, p. 750-757.

Research output: Contribution to journalArticle

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