Dopamine D₃ 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

Abstract

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.

Differential regulation of proliferation and neuronal differentiation in adult rat spinal cord neural stem/progenitors by ERK1/2, Akt, and PLCγ

“…In contrast, the activation of either Akt or ERK1/2 has been shown to promote proliferation in adult hippocampal (Peltier et al, 2007; Ma et al, 2009) and in adult subventricular zone (Torroglosa et al, 2007; Lao et al, 2013) neural stem cell cultures. Similarly, in adult spinal cord NSPC cultures, we have shown that the inhibition of either the PI3K/Akt pathway or the MEK/ERK1/2 pathway, but not the PLCγ pathway, markedly reduced cell division (proliferation).…”

The role of dopamine in huntington's disease

“…Indeed, the close proximity of the subventricular zone with the striatum makes it a potential source of endogenous neurons that could be engaged in brain repair strategies for this neurodegenerative disease. The dense DA innervation of the subventricular zone observed in HD brains indicates that this monoamine, known to exert a robust excitatory influence upon adult neurogenesis (Baker et al, 2004; Hoglinger et al, 2004; Van Kampen et al, 2004; Lao et al, 2013), might significantly contribute to cell proliferation in HD and could have a crucial role in intrinsic mechanisms involved in attempts to produce new neurons in order to compensate for the massive striatal neuronal losses that occur. It could also play a role in striatal gliogenesis that takes place in such a pathological condition (Sapp et al, 2001).…”

Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

“…Our study suggests a potential involvement of AT 2 in each of these stages. The proliferative, survival, and prodifferentiation effects of CGP42112A may be attributed, at least in part, to the observed early elevation of the neurotrophins (e.g., BDNF and NGF) and their downstream effectors ERK1/2 and Akt [29,70,[81][82][83]. Of note, as BrdU injections were given at early time points after TBI, when apoptotic events still take place [42], we cannot entirely exclude the possibility of false-positive labeling of neurons undergoing apoptosis.…”