Dopamine D 3 receptor activation promotes neural stem/progenitor cell proliferation through AKT and ERK1/2 pathways and expands type‐B and ‐C cells in adult subventricular zone

The neurotransmitter dopamine acts on the subventricular zone (SVZ) to regulate both prenatal and postnatal neurogenesis, in particular through D 3 receptor (D 3 R) subtype. In this study, we explored the cellular mechanism(s) underlying D 3 R‐mediated cell proliferation and tested if systemic delivery of a D 3 R agonist would induce SVZ multipotent neural stem/precursor cell (NSC/NPC) proliferation in vivo . We found that treatment with the D 3 R agonist, 7‐OH‐DPAT, enhances cell proliferation in a dose‐dependent manner in cultured SVZ neurospheres from wild‐type, but not D 3 R knock‐out mice. Furthermore, D 3 R activation also stimulates S‐phase and enhances mRNA and protein levels of cyclin D1 in wild‐type neurospheres, a process which requires cellular Akt and ERK1/2 signaling. Moreover, chronic treatment with low dose 7‐OH‐DAPT in vivo increases BrdU + cell numbers in the adult SVZ, but this effect was not seen in D 3 R KO mice. Additionally, we probed the cell type specificity of D 3 R agonist‐mediated cell proliferation. We found that in adult SVZ, GFAP + astrocytes, type‐B GFAP + /nestin + and type‐C EGF receptor (EGFR + )/nestin + cells express D 3 R mRNA, but type‐A Doublecortin (Dcx) + neuroblasts do not. Using flow cytometry and immunofluorescence, we demonstrated that D 3 R activation increases GFAP + type‐B and EGFR + type‐C cell numbers, and the newly divided Dcx + type‐A cells. However, BrdU + /Dcx + cell numbers were decreased in D 3 R KO mice compared to wildtype, suggesting that D 3 R maintains constitutive NSC/NPCs population in the adult SVZ. Overall, we demonstrate that D 3 R 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. © 2013 Wiley Periodicals, Inc.