Distinct Roles of Selenoproteins in Facilitating Synaptic Plasticity for Learning and Memory.

Abstract

Selenium (Se) is a micronutrient essential for life and important for proper neurological and immune function, reproductive viability, and cardiovascular health. In the body, it acts through incorporation into selenoproteins, which can function as antioxidants that protect cells from oxidative damage and maintain many other cellular functions. This dissertation focused on the roles of Selenoprotein P and M (Sepp1 and SelM) in learning and memory. Sepp1 is primarily thought to transport Se to the tissues, including the brain, for synthesis of other selenoproteins. Sepp1 has been shown to colocalize with amyloid beta plaques in postmortem brains from patients diagnosed with Alzheimer’s disease (AD) (1). Sepp1-/- mice on selenium deficient diets have severe neurological impairments with major motor function deficits, and impaired hippocampal dependent synaptic function and memory, similar to deficits seen in AD. We hypothesize that Sepp1 has a localized function in the brain, independent of its function in transporting selenium to the brain and other body tissues. SelM has antioxidant properties and is highly expressed in the brain (2). The hippocampus, one of the areas in which SelM is expressed, is involved in learning and memory acquisition. A study using an AD mouse model having a mutant form of presenilin-2 resulted in suppression of SelM expression (3). We report here that SelM-/- male, but not female mice, lack hippocampal long-term potentiation (LTP), which is a cellular model for learning and memory. These results suggest that SelM has an integral sex-specific role in synaptic plasticity, learning and memory. To determine the direct role for Sepp1 in the brain, we developed a novel mouse model that has restored SEPP1 expression in forebrain neurons of Sepp1-/- mice. The successful restoration of LTP in Sepp1-/- mice with locally restricted SEPP1 gene rescue to forebrain neurons highlights the critical role Sepp1 plays in synaptic plasticity as well as enabling synthesis of SelM and other selenoproteins that are required for learning and memory. We elucidate the important neuroprotective properties of these selenoproteins in memory and learning, serving as a foundation for further studies to understand their roles in Alzheimer's disease and other neurodegenerative disorders.