Nmda Receptors In Hibernating Arctic Ground Squirrels

Abstract

Hibernation is a unique physiological state characterized by suppressed metabolism and body temperature that is interrupted by multiple, brief periods of arousal throughout the hibernation season. Blood flow fluctuates during hibernation and arousal in a reperfusion-like manner without causing neurological damage. Previous studies show that hippocampal slices from hibernating animals tolerate experimental oxygen nutrient deprivation and N-methyl-D-aspartate (NMDA) toxicity better than slices from euthermic animals. However, the cellular mechanisms underlying these examples of tolerance remain unclear. Tolerance to NMDA toxicity suggests that modulation of NMDA receptors (NMDAR) contributes to intrinsic tissue tolerance in slices from hibernating Arctic ground squirrels (hAGS, Spermophilus parryii). NMDAR are one subtype of glutamate receptors. NMDAR play critical roles in excitatory synaptic transmission, synaptic plasticity, learning and memory, and excitotoxicity. NMDAR1 (NR1) is a fundamental subunit of NMDAR and required for receptor function. The main focus of the current project was to test the hypothesis that NMDAR are down-regulated in hAGS compared with interbout euthermic AGS (ibeAGS) and to explore the potential mechanisms of this down-regulation. NMDAR function can be modulated by protein phosphorylation, subunit composition, and internalization. Hence, the aim of chapter 2 was to determine the distribution of NRl in hAGS and ibeAGS using immunohistochemistry. The aim of chapter 3 was to examine NMDAR function in cultured hippocampal slices from hAGS, ibeAGS, and rats using calcium imaging, and to investigate potential modulation of NMDAR such as phosphorylation and internalization for altered function using western blot analysis. Given that synaptic remodeling and functional changes after arousal from hibernation, and NMDAR play an important role in learning and memory, the aim of chapter 4 was to address the effects of hibernation on learning and memory in AGS using an active avoidance task. Here, we report that NMDAR in hAGS are down-regulated via decreased phosphorylation of NR1. This down-regulation is not due to changes in NR1 distribution and internalization. In addition, the fraction of NR1 in the functional membrane pool in AGS is less than in rats. These findings provide evidence that modulation of NMDAR contributes to neuroprotection observed in hAGS.