Date of Award
Summer 2025
Document Type
Open Access Dissertation
Department
Biomedical Science
First Advisor
Joseph A. McQuail
Abstract
D-serine, the primary co-agonist for synaptic NMDARs, and as such is critical for learning, synaptic plasticity, neural network regulation. During aging, brain D-serine concentration decrease which could explain the age-associated cognitive deficits and impaired NMDAR activation and synaptic plasticity. As a result, in this study we investigated the effects of age on the effectors of the D-serine biosynthesis pathway to better understand the mechanisms that drive reduced D-serine availability as well as a efficacy of therapeutic that has mechanistic potential to improve memory in aging individuals by preventing the degradation of D-serine and therefore potentiating NMDAR activation. To test this, we characterized the performance of young adult (6-months-old) and older-aged (24-months-old) F344 rats in a place-learning task in the Morris water maze. Following, we utilized a cohort of rats to quantify protein levels of serine racemase, the enzyme which catalyzes the conversion of L-serine into D-serine, as well as PHGDH, the catalyst of the rate-limiting step in L-serine synthesis. Our findings reveal that compared to young adult, older-aged rats have significantly lower serine racemase, but higher PHGDH in both the PFC and HPC. The other cohort of rats were trained no a delayed match-to-place task following initial water maze testing, and were subsequently treated with 3-Methylpyrazole-5-carboxylic acid, a D-amino acid oxidase inhibitor (DAOI). We observed a significant dose-dependent improvement on task performance in older-aged rats. In addition, we determined that DAOI treatment restores learning-associated ERK phosphorylation, an indirect marker of NMDAR activation, in both the PFC and HPC of older-aged rats. These results suggest that enhancing D-serine availability may be a useful approach for restoring cognitive performance in older-aged adults.
Rights
© 2025, David Janos Horovitz
Recommended Citation
Horovitz, D. J.(2025). Enhancing D-Serine Signaling Reverses Age-Related Cognitive and Neurobiological Deficits. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/8493