DPP4-deficient congenic rats display blunted stress, improved fear extinction and increased central NPY. (March 2015)

• Record Type: Journal Article
• Authors: Canneva, Fabio; Golub, Yulia; Distler, Joerg; Dobner, Julia; Meyer, Sandra; von Hörsten, Stephan
• Is Part Of: Psychoneuroendocrinology. Volume 53(2015:Mar.)
• Page Start: 195
• Page End: 206
• Publication Date: 2015-03
• Subjects: NPY -- Anxiety -- Stress -- Fear -- CD26 -- DPP4; Psychoneuroendocrinology -- Periodicals; Endocrinology -- Periodicals; Neurology -- Periodicals; Psychiatry -- Periodicals; Neuropsychoendocrinologie -- Périodiques; 616.8
• DOI: 10.1016/j.psyneuen.2015.01.007
• Languages: English
• ISSNs: 0306-4530

Abstract

Highlights: Congenic rat model deficient for dipeptidyl peptidase 4 (DPP4) activity. Lack of DPP4 is associated with increased CNS NPY and stress tolerance. DPP4-deficient rats also display improved extinction of learned fear. Increased central NPY and diminished stress/fear are associated to DPP4 deficiency. Summary: Background: Inhibitors of dipeptidyl peptidase 4 (DPP4, CD26) are used for the treatment of type 2 diabetic patients and better glucose tolerance has been confirmed in functionally DPP4-deficient congenic rats (DPP4mut), along with immunological alterations and, interestingly, a stress-resilient phenotype. All these findings are in agreement with the "moonlighting" properties of DPP4, whose proteolytic action is responsible for the inactivation of a number of regulatory peptides including, but not limited to, neuropeptide Y (NPY). Among all candidate substrates, DPP4 displays highest affinity for NPY, an endogenous anxiolytic neurotransmitter that is suggested as a candidate biomarker in post-traumatic stress disorder (PTSD) and depression. Methods and results: Central and peripheral NPY levels were measured by ELISA in DPP4mut and DAwt rats revealing a significantly higher concentration of the peptide in the CSF of DPP4mut animals. This finding positively correlated with the blunted stress phenotype measured on an analgesia-meter. Additionally, when a classical fear-conditioning paradigm was investigated, short-term fear extinction was significantly potentiated in DPP4mut rats as compared to wt controls. Conclusions: Our findings indicate a positive correlation between reduced stress-responsiveness and increased central NPY, in DPP4mut rats. Most interestingly, the behavioral phenotype extends to facilitation of fear extinction. These observations raise further interest in DPP4-modulating drugs for the potential effect on NPY metabolism, as a therapeutic tool for psychiatric conditions such as anxiety disorders and PTSD.