Melanocortin-receptor 4 activation modulates proliferation and differentiation of rat postnatal hippocampal neural precursor cells

Postnatal hippocampal neurogenesis is essential for learning and memory. Hippocampal neural precursor cells (NPCs) can be induced to proliferate and differentiate into either glial cells or dentate granule cells. Notably, hippocampal neurogenesis decreases dramatically with age, partly due to a reduction in the NPC pool and a decrease in their proliferative activity. Alpha-melanocyte-stimulating hormone (α-MSH) improves learning, memory, neuronal survival and plasticity. Here, we used postnatally-isolated hippocampal NPCs from Wistar rat pups (male and female combined) to determine the role of the melanocortin analog [Nle⁴, D-Phe⁷]-α-MSH (NDP-MSH) in proliferation and fate acquisition of NPCs. Incubation of growth-factor deprived NPCs with 10 nM NDP-MSH for 6 days increased the proportion of Ki-67- and 5-bromo-2′-deoxyuridine (BrdU)-positive cells, compared to the control group, and these effects were blocked by the MC4R antagonist JKC-363. NDP-MSH also increased the proportion of glial fibrillar acidic protein (GFAP)/Ki-67, GFAP/sex-determining region Y-box2 (SOX2) and neuroepithelial stem cell protein (NESTIN)/Ki-67-double positive cells (type-1 and type-2 precursors). Finally, NDP-MSH induced peroxisome proliferator-activated receptor (PPAR)-γ protein expression, and co-incubation with the PPAR-γ inhibitor GW9662 prevented the effect of NDP-MSH on NPC proliferation and differentiation. Our results indicate that in vitro activation of MC4R in growth-factor-deprived postnatal hippocampal NPCs induces proliferation and promotes the relative expansion of the type-1 and type-2 NPC pool through a PPAR-γ-dependent mechanism. These results shed new light on the mechanisms underlying the beneficial effects of melanocortins in hippocampal plasticity and provide evidence linking the MC4R and PPAR-γ pathways in modulation of hippocampal NPC proliferation and differentiation.