Zhang Tingting, Hong Juan, Di Tingting, Chen Ling
State Key Lab of Reproductive Medicine, Nanjing Medical UniversityNanjing, China; Department of Physiology, Nanjing Medical UniversityNanjing, China.
Department of Physiology, Nanjing Medical University Nanjing, China.
Front Mol Neurosci. 2016 Oct 13;9:101. doi: 10.3389/fnmol.2016.00101. eCollection 2016.
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 Ca/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.
帕金森病（PD）的特征是伴有抑郁的运动症状。我们评估了多巴胺能耗竭对海马神经发生过程的影响，以探究抑郁产生的机制。连续五天给小鼠注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）（MPTP小鼠）可减少海马齿状回（DG）中的多巴胺能纤维。MPTP小鼠在之后的2-3周内表现出类似抑郁的行为。在最后一次注射MPTP后4小时注射溴脱氧尿苷（BrdU）。在注射BrdU后的第1天（D1）、第7天（D7）、第14天（D14）和第21天（D21）检查背侧（d-DG）和腹侧（v-DG）DG中的BrdU阳性（BrdU）细胞。与对照组相比，在MPTP小鼠的v-DG中发现的D7、D14和D21期BrdU细胞或BrdU/NeuN细胞较少，但D1期BrdU细胞数量无差异。然而，d-DG中的BrdU细胞数量在两者之间没有差异。在MPTP小鼠的v-DG中观察到双皮质素阳性（DCX）细胞减少。MPTP小鼠v-DG中的蛋白激酶A（PKA）和钙/环磷酸腺苷反应元件结合蛋白（CREB）磷酸化水平降低，1型多巴胺受体（D1R）激动剂SKF38393可使其逆转，但2型多巴胺受体（D2R）激动剂喹吡罗则不能。在注射BrdU后的第2-7天用SKF38393治疗MPTP小鼠可减少v-DG中D7和D21期BrdU细胞的损失，并改善类似抑郁的行为；这些变化对PKA抑制剂H89敏感。此外，在MPTP小鼠的v-DG中注射SKF38393可减少D21期BrdU细胞的损失并缓解类似抑郁的行为。在对照小鼠中，SCH23390阻断D1R会导致v-DG中D21期BrdU细胞减少和出现类似抑郁的行为。我们的结果表明，MPTP诱导的多巴胺能耗竭损害了v-DG中D1R介导的新生神经元的早期存活，从而产生类似抑郁的行为。
