A comparative study of blood and hippocampal D-serine change patterns in drug-naïve patients and animal models of depression

Abstract

The dysfunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated in depression, and D‑serine, an endogenous co-agonist of NMDAR, plays a critical role in its function. However, the pattern and relationship of alterations in central and peripheral D‑serine concentrations in depression remain unclear. In this study, we conducted two parallel cross-sectional studies to investigate D‑serine alterations in depression. In the clinical study, we recruited drug-naïve patients with major depressive disorder (MDD) and age and sex-matched healthy controls to assess peripheral D‑serine levels in serum. In the preclinical study, a chronic social defeat stress (CSDS) mouse model of depression was used to measure both peripheral and hippocampal D‑serine levels, given the hippocampus's key role in depression. Our results revealed significantly higher levels of D‑serine and the D‑serine/L‑serine ratio in the serum of MDD patients compared to controls, while L‑serine levels showed no significant differences. Similarly, in the CSDS mouse model, serum D‑serine levels were also increased. However, hippocampal D‑serine and L‑serine levels were decreased in depressed mice compared to controls, with no significant correlation observed between blood and hippocampal D‑serine levels. These findings suggest a potential pattern of D‑serine concentrations between peripheral blood and the hippocampus in depression. However, the clinical implications of contrasting changes in D‑serine in the peripheral and central systems, as well as the underlying mechanisms, require further investigation.