An Investigation of Sigma-1 Receptor Involvement in Glutamatergic Synaptic Physiology, Implications for Alzheimer’s Disease

Abstract

The sigma-1 receptor (sig-1R) is a unique endoplasmic reticulum (ER) chaperone protein that interacts with a variety of voltage- and ligand-gated ion channels, which are components of an intricate system that regulates neuronal functioning. While there is an extensive body of knowledge pertaining to the sig-1R, many questions remain. The first question this thesis addresses is how the sig-1R modulates the functioning of the N-methyl-D-aspartate receptor (NMDAR). Using a heterologous expression system, I provide evidence that the mechanism of modulation is likely not a direct interaction between sig-1R and NMDAR and that this is not affected by the presence or absence of the membrane-associated guanylate kinases (MAGUK) protein PSD-95. The next question addressed investigates the impact of sig-1R absence on the synaptic physiology and action potential firing of CA1 pyramidal neurons. It was found that there is not a significant difference in these parameters, suggesting a non-essential role of the sig- 1R under normal physiological conditions. The third topic covered in my studies explores the sig-1R KO mouse in the Aβ25-35 infusion model of Alzheimer’s disease (AD). Preliminary results suggest that there is a dysfunction in the action potential characteristics and after- hyperpolarization characteristics of challenged sig-1R KO mice. Overall my results provide the groundwork for future experiments that will lead to a better understanding of the sig-1R and its role in cellular and synaptic physiology.