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 GluRzeta subunit (NR1) combined with any one of four GluRepsilon subunits (GluRepsilon1-GluRepsilon4; NR2A-NR2D). Although the GluRzeta subunit exists in the majority of the CNS throughout all stages of development, the GluRepsilon subunits are expressed in distinct temporal and spatial patterns. In the present study, we investigated neuronal functions in mice lacking the embryonic GluRepsilon4 subunit. GluRepsilon4 mutant mice exhibited reductions of [(3)H]MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] binding and (45)Ca(2+) uptake through the NMDA receptors. The expression of GluRzeta subunit protein, but not GluRepsilon1 and GluRepsilon2 subunit proteins, was reduced in the frontal cortex and striatum of the mutant mice. A postmortem examination in GluRepsilon4 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. GluRepsilon4 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 GluRepsilon4 mutant mice have dysfunctional NMDA receptors and altered emotional behavior probably caused by changes in monoaminergic neuronal activities in adulthood.

GluN2D Subunit-Containing NMDA Receptors Control Tissue Plasminogen Activator-Mediated Spatial Memory

“…Our results show a decrease in spontaneous locomotor activity and in emotional memory in GluN2D-deficient mice as described previously by other authors (Ikeda et al, 1995;Miyamoto et al, 2002;Hagino et al, 2010). In addition, we evidenced that GluN2D-deficient mice exhibited low performances in the place recognition task because they do not discriminate the newly open arm and one familiar arm.…”

“…Thus, the first step of our present study was to confirm (Ikeda et al, 1995;Miyamoto et al, 2002;Hagino et al, 2010) and extend the behavioral phenotype of GluN2D-deficient mice by the use of various tests, such as actimetry, contextual fear conditioning, and place recognition task. Our results show a decrease in spontaneous locomotor activity and in emotional memory in GluN2D-deficient mice as described previously by other authors (Ikeda et al, 1995;Miyamoto et al, 2002;Hagino et al, 2010).…”

Neuronal mechanism of nociceptin-induced modulation of learning and memory: Involvement of N-methyl-D-aspartate receptors

“…[ 3 H]MK-801 binding was measured as described previously. 19,20 Briefly, frozen samples were thawed at room temperature and homogenized in 40 volumes of 50 mM Tris-acetate buffer (pH 7.4) containing 1 mM EDTA using a sonicator. All further procedures were performed at 41C.…”

The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release

“…For depolarization stimulation, 60 mM KCl containing aCSF was delivered through the dialysis probe for 20 min. Dopamine levels in the dialysates were analyzed as described (33). For the rescue study with tPA and plasmin, a dialysis probe equipped with a microinjection tube (MIA-8-1; 1 mm membrane length, EICOM) was used (34).…”