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The Journal of Neuroscience, March 15, 2002, 22(6):2335-2342

Lower Sensitivity to Stress and Altered Monoaminergic Neuronal Function in Mice Lacking the NMDA Receptor 4 Subunit

Yoshiaki Miyamoto¹, Kiyofumi Yamada¹, Yukihiro Noda¹, Hisashi Mori², Masayoshi Mishina², and Toshitaka Nabeshima¹

¹ Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8560, Japan, and ² Department of Molecular Neurobiology and Pharmacology, School of Medicine, University of Tokyo, Bunkyou-Ku, Tokyo 113-0033, Japan

NMDA receptors, an ionotropic subtype of glutamate receptors (GluRs), play an important role in excitatory neurotransmission, synaptic plasticity, and brain development. They are composed of the GluR subunit (NR1) combined with any one of four GluR subunits (GluR1-GluR4; NR2A-NR2D). Although the GluR subunit exists in the majority of the CNS throughout all stages of development, the GluR subunits are expressed in distinct temporal and spatial patterns. In the present study, we investigated neuronal functions in mice lacking the embryonic GluR4 subunit. GluR4 mutant mice exhibited reductions of [³H]MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] binding and ⁴⁵Ca²⁺ uptake through the NMDA receptors. The expression of GluR subunit protein, but not GluR1 and GluR2 subunit proteins, was reduced in the frontal cortex and striatum of the mutant mice. A postmortem examination in GluR4 mutant mice revealed that tissue contents of norepinephrine, dopamine, serotonin, and their metabolites were reduced in the hippocampus and that dopamine, as well as serotonin, metabolism was upregulated in the frontal cortex, striatum, hippocampus, and thalamus. To clarify the phenotypical influences of the alteration in neuronal functions, performances in various behavioral tests were examined. GluR4 mutant mice showed reduced spontaneous locomotor activity in a novel environment and less sensitivity to stress induced by the elevated plus-maze, light-dark box, and forced swimming tests. These findings suggest that GluR4 mutant mice have dysfunctional NMDA receptors and altered emotional behavior probably caused by changes in monoaminergic neuronal activities in adulthood.

Key words: NMDA receptor; GluR4 subunit; GluR subunit; monoaminergic neuronal systems; locomotor activity; emotional behavior

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2262335-08$05.00/0

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