Abstract

Neuropeptide processing enzymes of the regulated secretory pathway are decreased in the anterior hippocampus of postmortem depressed subjects

Waselus M, Medina A, Turner CA, Bunney WE, Myers RM, Schatzberg AF, Barchas JD, Akil H, Watson SJ
Society for Neuroscience. 2017.

Numerous neuropeptides have been implicated in the pathophysiology of major depressive disorder (MDD). Unlike the biosynthesis of classical neurotransmitters, neuropeptides must go through a series of processing steps to release active neuropeptide(s) from their larger, inactive precursors. The first enzymatic step in this process is carried out by a family of proprotein/prohormone convertases (PCs), which typically cleave inactive peptide precursors C-terminal to paired basic amino acid residues (e.g., Lys/Arg). Two members of the PC family, PC1/3 and PC2, are stored in secretory granules and act on peptide precursors that are processed in the regulatory secretory pathway. Early in the secretory pathway, the activity of PC1/3 and PC2 can be modified when bound by their associated binding proteins, proSAAS (PC1/3) and 7B2 (PC2). We have previously shown that 7B2 was decreased in specific posterior hippocampal subregions of depressed subjects compared to controls. Here, we extended these studies to examine the distribution and expression of these enzymes in the anterior hippocampus of both control and depressed subjects. Frozen 10µm sections through the anterior hippocampus were processed for in situ hybridization using radiolabeled cRNA probes for PC1/3, PC2, proSAAS and 7B2, with subsequent quantification of mRNA expression measured in the dentate gyrus (DG), hippocampus proper (CA1, CA2, CA3, and CA4) and subicular complex (prosubiculum, subiculum and presubiculum). Decreased expression of PC1/3 and PC2 was identified within specific subregions of the typical component (Ding and Van Hoesen, 2015) of the anterior hippocampus in depressed subjects. Differences in the expression of proSAAS and 7B2 between control and MDD subjects were not detected in any region examined. Unfortunately, it is difficult to predict and/or determine with certainty the specific complement of peptides that may be impacted by these decreases in PC1/3 and PC2 due to the indiscriminate nature of these enzymes. However, given that PC1/3 and PC2 are the primary endopeptidases responsible for neuropeptide processing in the regulated secretory pathway, our findings suggest that there may be widespread dysregulation in the early processing steps of regulated neuropeptides, specifically in the anterior hippocampus, in depressed subjects. Furthermore, together with our previous findings of decreased 7B2 expression in the posterior hippocampus, it is apparent that there exists both molecular and anatomical specificity in the dysregulation of neuropeptide processing enzymes in the postmortem hippocampus of depressed individuals.

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