Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor ε4 subunit

Abstract

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 GluRζ subunit (NR1) combined with any one of four GluRε subunits (GluRε1-GluRε4; NR2A-NR2D). Although the GluRζ subunit exists in the majority of the CNS throughout all stages of development, the GluRε subunits are expressed in distinct temporal and spatial patterns. In the present study, we investigated neuronal functions in mice lacking the embryonic GluRε4 subunit. GluRε4 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 GluRζ subunit protein, but not GluRε1 and GluRε2 subunit proteins, was reduced in the frontal cortex and striatum of the mutant mice. A postmortem examination in GluRε4 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. GluRε4 mutant mice showed reduced spontaneous locomotor activity in a novel environment and less sensitivity to stress induced by the elevated plus-maze, lightdark box, and forced swimming tests. These findings suggest that GluRε4 mutant mice have dysfunctional NMDA receptors and altered emotional behavior probably caused by changes in monoaminergic neuronal activities in adulthood.