A developmental influence of the N-methyl-D-aspartate receptor NR3A subunit on prepulse inhibition of startle

Background: The N-methyl-D-aspartate (NMDA) receptor is composed of various conformations of multiple subunits (including N-R1, NR2A-D, and NR3A-B). Peak expression of the NR3A subunit occurs approximately 2-3 weeks postnatal, with low levels in adulthood, In the brain, the NR3A subunit is localized primarily in the amygdala, hippocampus, striatum, and cortex. These regions are involved in the modulation of prepulse inhibition of startle (PPI), an operational measure of sensorimotor gating that is modulated by NMDA receptors. NR3A reduces NMDA current in native neurons expressing NR1 and NR2 subunits and forms glycine receptors when expressed with NR1 in the absence of NR2 in both oocyte and mammalian expression systems. Methods: To examine the role of NR3A in vivo, NR3A knockout (KO), and overexpressing transgenic mice were generated. Adult NR3A overexpressing mice exhibited normal PPI; PPI in NR3A KO mice was tested repeatedly from weaning through adulthood. Results: Male NR3A KO mice exhibited an increase in PPI at 3 and 4 weeks postnatal, whereas female NR3A KO mice did not differ from their WT counterparts at any age tested. Conclusions: This sex-specfic increase in PPI is consistent with the antagonistic role of the NR3A subunit in NMDA receptor function and with the observation that estrogen modulates NMDA receptor function.