Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice

• Published in: The Journal of biological chemistry Vol. 290; no. 33; pp. 20488 - 20498
• Main Authors: Beckman, Danielle, Santos, Luis E., Americo, Tatiana A., Ledo, Jose H., de Mello, Fernando G., Linden, Rafael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-08-2015; American Society for Biochemistry and Molecular Biology
• Subjects: Alzheimer disease; Animals; Behavior, Animal; Biogenic Monoamines - physiology; cerebral cortex; depression; Depression - physiopathology; Mice; Mice, Inbred C57BL; Mice, Knockout; monoaminergic neurotransmission; Neurobiology; neurodegeneration; prion; prion disease; PrPC Proteins - genetics; PrPC Proteins - physiology; cerebral cortex; prion disease; Alzheimer disease; neurodegeneration; prion; depression; monoaminergic neurotransmission
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.666156

We sought to examine interactions of the prion protein (PrPC) with monoaminergic systems due to: the role of PrPC in both Prion and Alzheimer diseases, which include clinical depression among their symptoms, the implication of monoamines in depression, and the hypothesis that PrPC serves as a scaffold for signaling systems. To that effect we compared both behavior and monoaminergic markers in wild type (WT) and PrPC-null (PrP−/−) mice. PrP−/− mice performed poorly when compared with WT in forced swimming, tail suspension, and novelty suppressed feeding tests, typical of depressive-like behavior, but not in the control open field nor rotarod motor tests; cyclic AMP responses to stimulation of D1 receptors by dopamine was selectively impaired in PrP−/− mice, and responses to serotonin, but not to norepinephrine, also differed between genotypes. Contents of dopamine, tyrosine hydroxylase, and the 5-HT5A serotonin receptor were increased in the cerebral cortex of PrP−/−, as compared with WT mice. Microscopic colocalization, as well as binding in overlay assays were found of PrPC with both the 5HT5A and D1, but not D4 receptors. The data are consistent with the scaffolding of monoaminergic signaling modules by PrPC, and may help understand the pathogenesis of clinical depression and neurodegenerative disorders.
Background: The prion protein (PrPC) functions as a scaffold for cell surface signaling systems, and plays a role in neurodegenerative diseases that include clinical depression among their symptoms.
Results: PrPC-null mice showed depressive-like behavior concomitant with functional changes in monoaminergic systems.
Conclusion: PrPC regulates functions of monoaminergic synapses.
Significance: PrPC may be involved in major depression and related neuropsychiatric disorders.