TRANSCRIPTOMIC EXAMINATION OF IMMATURE GRANULE NEURONS IN THE DEPRESSED HUMAN DENTATE GYRUS

The generation of new granule cells in the dentate gyrus (DG) of the hippocampus has been reported to be implicated in depression and antidepressant efficacy, a theory known as the neurogenic hypothesis of depression. Recently, our group has demonstrated that immature granule cells persist in the adult human DG, despite low levels of neurogenesis. Here, we aim to provide new insight into the involvement of these immature cells in major depressive disorder (MDD) at the transcriptomic level. Utilizing post-mortem tissue from frozen-fixed anterior DG samples of adult non-psychiatric and depressed individuals who have died by suicide, we performed single-molecule fluorescent in situ hybridization (RNAscope) to examine immature PROX1⁺CALB2⁺DCX⁺ neurons in the granule cell layer (GCL), subgranular zone (SGZ), and outside the neurogenic niche, testing the hypothesis that these cells are altered in MDD. Our preliminary findings indicate trends toward fewer DG DCX⁺ cells in MDD patients without antidepressant treatment compared to controls and increased number of these cells in treated MDD subjects compared to control and untreated MDD subjects. Quantitative analysis also revealed a significant increase in the percentage of SGZ PROX1⁺CALB2⁺DCX⁺ cells in treated MDD subjects compared to psychiatrically healthy individuals. These immature cells displayed in MDD a different distribution within the GCL (inner vs outer GCL) compared to controls. Additionally, an abnormal distribution of granule cells was observed in MDD subjects, reflected by ectopic immature and PROX1⁺CALB1⁺DCX^- granule cells. Our preliminary findings suggest that immature granule neurons are altered in MDD and play a role in antidepressant action.