Dopamine D3 Receptors: Regulation of Adult Neural Stem Cell Proliferation and Involvement in Parkinson's Disease

• Main Authors: Chu Lan Lao, 劉珠蘭
• Other Authors: J. C. Chen
• Format: Others
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/09230289041787875551

博士 === 長庚大學 === 生物醫學研究所 === 101 === The neurotransmitter dopamine acts on the subventricular zone (SVZ) to regulate both prenatal and postnatal neurogenesis, in particular through D3 receptor (D3R) subtype. In this study, we explored the cellular mechanism(s) underlying D3R-mediated cell proliferation and tested if systemic delivery of a D3R agonist would induce SVZ NSC/NPC proliferation in vivo. We found that treatment with the D3R agonist, 7-OH-DPAT, enhances cell proliferation in a dose-dependent manner in cultured SVZ neurospheres from wild-type, but not D3R knock-out (KO) mice. Further, we demonstrate that D3R activation induces NSC/NPC proliferation through Akt and ERK1/2 signaling and increases the numbers of type-B and -C NSC/NPCs in the adult SVZ. On the other hand, Parkinson’s disease is a neurodegenerative disease with a hallmark motor defect caused by the death of dopaminergic neurons in the substantia nigra and neurodegeneration of striatal dopamine terminals of which locate on the side of SVZ. Thus, we speculate SVZ adult neurogenesis may have chance to provide protective and repair effect in PD. To this purpose, first, we investigated the neuroprotection and neurorestoration effect of dopamine D3R agonists on MPTP-induced Parkinson’s disease mouse model and employed D3R KO mice to validate if neuroprotective effect is D3R-dependent. We found that in wild type mice, but not D3R KO mice, D3R agonists rescue dopamine depletion in the striatum as well as dopamine neuronal death in the substantia nigra after MPTP-treatment. Next, we used 4%AraC infusion into lateral ventricle in order to inhibit the neurogenesis to validate if D3R-induced dopamine functional restoration in PD requires NSC/NPC proliferation. The results of TH-ir in the striatum indicated that the rescuing effect of D3R agonist was completely lost after SVZ neural stem cell inhibition . All together, we demonstrate that D3R activation would evoke SVZ NSC/NPC proliferation with specific cell types and D3R agonist-dependent neuroprotection seems to recruit NSC/NPC to repair the functional loss of PD mice.