title: MPTP Impairs Dopamine D1 Receptor-Mediated Survival of Newborn Neurons in Ventral Hippocampus to Cause Depressive-Like Behaviors in Adult Mice.
abstract: Parkinson's disease (PD) is characterized by motor symptoms with depression. We evaluated the influence of dopaminergic depletion on hippocampal neurogenesis process to explore mechanisms of depression production. Five consecutive days of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection in mice (MPTP-mice) reduced dopaminergic fibers in hippocampal dentate gyrus (DG). MPTP-mice exhibited depressive-like behaviors later for 2-3 weeks. BrdU was injected 4 h after last-injection of MPTP. BrdU-positive (BrdU+) cells in dorsal (d-DG) and ventral (v-DG) DG were examined on day 1 (D1), 7 (D7), 14 (D14) and 21 (D21) after BrdU injection. Fewer D7-, D14- and D21-BrdU+cells or BrdU+/NeuN+cells, but not D1-BrdU+cells, were found in v-DG of MPTP-mice than in controls. However, the number of BrdU+cells in d-DG did not differ between the both. Loss of doublecortin-positive (DCX+) cells was observed in v-DG of MPTP-mice. Protein kinase A (PKA) and Ca2+/cAMP-response element binding protein (CREB) phosphorylation were reduced in v-DG of MPTP-mice, which were reversed by D1-like receptor (D1R) agonist SKF38393, but not D2R agonist quinpirole. The treatment of MPTP-mice with SKF38393 on days 2-7 after BrdU-injection reduced the loss of D7- and D21-BrdU+cells in v-DG and improved the depressive-like behaviors; these changes were sensitive to PKA inhibitor H89. Moreover, the v-DG injection of SKF38393 in MPTP-mice could reduce the loss of D21-BrdU+cells and relieve the depressive-like behaviors. In control mice, the blockade of D1R by SCH23390 caused the reduction of D21-BrdU+cells in v-DG and the depressive-like behaviors. Our results indicate that MPTP-reduced dopaminergic depletion impairs the D1R-mediated early survival of newborn neurons in v-DG, producing depressive-like behaviors.
authors: State Key Lab of Reproductive Medicine, Nanjing Medical UniversityNanjing, China; Department of Physiology, Nanjing Medical UniversityNanjing, China.
authors: Tingting
authors: T
authors: Zhang
authors: State Key Lab of Reproductive Medicine, Nanjing Medical UniversityNanjing, China; Department of Physiology, Nanjing Medical UniversityNanjing, China.
authors: Juan
authors: J
authors: Hong
authors: Department of Physiology, Nanjing Medical University Nanjing, China.
authors: Tingting
authors: T
authors: Di
authors: State Key Lab of Reproductive Medicine, Nanjing Medical UniversityNanjing, China; Department of Physiology, Nanjing Medical UniversityNanjing, China.
authors: Ling
authors: L
authors: Chen
keywords: Parkinson’s disease (PD); depression; dopaminergic receptor (DR); hippocampal dentate gyrus (DG); neurogenesis