Expression of NR1, NR2A and NR2B NMDA receptor subunits is not altered in the genetically-inbred Balb/c mouse strain with heightened behavioral sensitivity to MK-801, a noncompetitive NMDA receptor antagonist

Abstract

The genetically-inbred Balb/c mouse strain shows heightened sensitivity to the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to raise the threshold voltage necessary to precipitate tonic hindlimb extension and elicit irregular episodes of intense jumping behavior (referred to as “popping”), relative to other inbred mouse strains and the outbred NIH Swiss mouse. Moreover, an allosteric modulatory effect of sarcosine, a glycine reuptake inhibitor, on MK-801′s antagonism of electrically precipitated seizures was detected 24 h after Balb/c mice were forced to swim in cold water for up to 10 min; this was not observed in unstressed Balb/c mice or stressed or unstressed NIH Swiss mice. Phencyclidine (PCP), a noncompetitive NMDA receptor antagonist that binds to the same hydrophobic channel domain as MK-801, precipitates a schizophreniform psychosis in susceptible individuals that shares descriptive similarities with schizophrenia. This observation has led to the hypothesis that NMDA receptor hypofunction (NRH) is involved in the pathophysiology of schizophrenia and the testing of pharmacotherapeutic strategies to facilitate NMDA receptor-mediated neurotransmission in patients with this disorder (e.g., glycine reuptake inhibitors). The heightened behavioral sensitivity of the Balb/c mouse to MK-801 suggests that this mouse strain may be a useful model to study “psychosis-proneness” and screen for positive allosteric modulators of NMDA receptor-mediated neurotransmission. Conceivably, strain differences in the pharmacology of the NMDA receptor are due to differences in the relative expression of individual NMDA receptor subunits to each other (i.e., combinatorial regulation). The current study compared the normal protein expression patterns of six of the eight identified splice variant isoforms of the NR1 NMDA receptor subunit, and NR2A and NR2B subunits in the hippocampus and cerebral cortex of Balb/c and NIH Swiss mice. The heightened behavioral sensitivity of the Balb/c genetically-inbred mouse strain to MK-801, compared to the outbred NIH Swiss mouse strain, does not appear to result from relative alterations of expression of these NMDA receptor protein subunits that were examined.