Microglia release activators of neuronal proliferation mediated by activation of mitogen‐activated protein kinase, phosphatidylinositol‐3‐kinase/Akt and delta–Notch signalling cascades

Abstract

Microglia, the resident macrophage of the brain, can release substances that aid neuronal development, differentiation and survival. We have investigated the effects of non-activated microglia on the survival of cultured rat cerebellar granule neurones. Microglial-conditioned medium, collected from primary rat microglial cultures, was used to treat 7-day-in-vitro neurones, and neuronal viability and proliferation was assessed following a further 1 or 7 days in culture. Microglialconditioned medium enhanced neuronal survival by up to 50% compared with untreated neurones and this effect was completely abated by pretreatment of the microglia with L-leucine methyl ester. The expression of the proliferation marker Ki-67 increased in neuronal cultures treated with microglial-conditioned medium suggesting enhanced proliferation of precursor neurones. Microglial-induced neuronal proliferation could be attenuated by specific inhibition of mitogen-activated protein kinase or phosphatidylinositol-3-kinase/Akt signalling pathways, and by selective fractionation and immunodepletion of the microglial-conditioned medium. Activation of the Notch pathway was enhanced as antibody against the Notch ligand, delta-1, prevented the microglial-induced neuronal proliferation. These results show that microglia release stable neurotrophic factors that can promote neuronal precursor cell proliferation.

In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia

“…It is possible that bFGF cooperates with other factors released from microglia, in promoting cell proliferation. Furthermore, a mitogenic effect of microglia released neurotrophic factors has been reported for granule neuron precursor cells (Morgan et al, 2004).…”

Neuroactive steroids, their metabolites, and neuroinflammation

“…This activated state also coincides with the production of soluble mediators both detrimental, such as pro-inflammatory cytokines, reactive oxygen species, and reactive nitrogen species (Sawada et al 1989, Moss & Bates 2001, Viviani et al 2001, Liu et al 2002, Tansey et al 2007, and beneficial (i.e. anti-inflammatory cytokines and tropic factors) (Morgan et al 2004, Liao et al 2005, Muller et al 2006Fig. 2).…”

Microglia Modulate Hippocampal Neural Precursor Activity in Response to Exercise and Aging

“…Proinflammatory microglia are generally associated with reduced neurogenesis, as in this state they produce reactive oxygen species and nitric oxide, and release proinflammatory cytokines (Monje et al, 2003;Nakanishi et al, 2007). Conversely, neuroprotective microglia stimulate neurogenesis through the release of antiinflammatory cytokines and growth factors (Aarum et al, 2003;Morgan et al, 2004;Battista et al, 2006;Butovsky et al, 2006;Walton et al, 2006;Ziv et al, 2006;Deierborg et al, 2010). However, the cellular and molecular pathways that mediate the positive effects of voluntary exercise are largely unknown, and whether exercise-induced microglial proliferation and/or altered activation status contribute to increased NPC activity also remains unclear (Vukovic et al, 2011).…”