PINK1 deficiency is associated with increased deficits of adult hippocampal neurogenesis and lowers the threshold for stress-induced depression in mice

Sandeep K. Agnihotri, Liuke Sun, Benjamin K. Yee, Ruifang Shen, Ravi S. Akundi, Lianteng Zhi, Marilyn J. Duncan, Wayne A. Cass, Hansruedi Büeler

Research output: Journal article publicationJournal articleAcademic researchpeer-review

6 Citations (Scopus)

Abstract

Parkinson's disease (PD) is characterized by motor impairments and several non-motor features, including frequent depression and anxiety. Stress-induced deficits of adult hippocampal neurogenesis (AHN) have been linked with abnormal affective behavior in animals. It has been speculated that AHN defects may contribute to affective symptoms in PD, but this hypothesis remains insufficiently tested in animal models. Mice that lack the PD-linked kinase PINK1 show impaired differentiation of adult-born neurons in the hippocampus. Here, we examined the relationship between AHN deficits and affective behavior in PINK1 −/− mice under basal (no stress) conditions and after exposure to chronic stress. PINK1 loss and corticosterone negatively and jointly affected AHN, leading to lower numbers of neural stem cells and newborn neurons in the dentate gyrus of corticosterone-treated PINK1 −/− mice. Despite increased basal AHN deficits, PINK1-deficient mice showed normal affective behavior. However, lack of PINK1 sensitized mice to corticosterone-induced behavioral despair in the tail suspension test at a dose where wildtype mice were unaffected. Moreover, after two weeks of chronic restraint stress male PINK1 −/− mice displayed increased immobility in the forced swim test, and protein expression of the glucocorticoid receptor in the hippocampus was reduced. Thus, while impaired AHN as such is insufficient to cause affective dysfunction in this PD model, PINK1 deficiency may lower the threshold for chronic stress-induced depression in PD. Finally, PINK1-deficient mice displayed reduced basal voluntary wheel running but normal rotarod performance, a finding whose mechanisms remain to be determined.

Original languageEnglish
Pages (from-to)161-172
Number of pages12
JournalBehavioural Brain Research
Volume363
DOIs
Publication statusPublished - 2 May 2019

Keywords

  • Adult hippocampal neurogenesis
  • Chronic stress
  • Depression
  • HPA axis
  • Parkinson's disease
  • PINK1

ASJC Scopus subject areas

  • Behavioral Neuroscience

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