Role of the NR2 subunit and its molecular motifs on memory and cognition and the physiological outcome after experimental intracerebral hemorrhage

Abstract

The N-methyl-0-aspartate receptor is the main coincidence detector in the brain. It is known to be necessary for many forms of learning and memory. Interestingly, the NR2 subunit composition of the NMDA receptor is modulated endogenously according to the location in the brain and the age of the animal, with the NR1 subunit being ubiquitously expressed. In the forebrain regions, including the cortex, hippocampus, striatum, and amygdala, the NR2A and NR2B subunits are the primary subunits expressed. While it is known that a high NR2B:NR2A ratio enhances memory and cognition, it is not directly known, the effects of a low NR2B:NR2A ratio. In this project, the effects of modulating the NR2A:NR2B ratio on multiple forms of learning and memory are explored by the use of a NR2A transgenic mouse. Our transgenic mice overexpress the NR2A subunit in the forebrain regions, driving the NR2A:NR2B ratio toward the expression of the NR2A. As the NR2B subunit is known to favor learning and memory; we also further explore the role of the N-terminal and membrane domains and the Cterminal domain in the observed enhancements. Our data indicate that a high NR2A:NR2B ratio constrains multiple forms of long-term memory in our transgenic animals. Additionally, we have observed additional forms of enhanced learning and memory in the NR28 transgenic mice that were not tested previously. We were able to show that the NR28 C-terminal tail, and thus the intracellular signaling cascades, is responsible for the enhancements seen in the NR28 animals. Using the NR2A and NR28 transgenic mice, we also investigated the long-held hypothesis that a low NR2B:NR2A ratio would be beneficial to hemorrhagic stroke recovery. Until now this hypothesis has only been investigated by the use of pharmaceuticals, whereby the NR28 subunit is antagonized. We found that while several physiological factors, including neurological deficit and survival rate were unchanged, lesion size and percent edema were significantly less in the NR2A transgenic mice than the NR28 transgenic mice. This demonstrates that a low NR2B:NR2A ratio may be beneficial for some aspects of hemorrhagic stroke recovery.