Ciliary Neurotrophic Factor Mediates Dopamine D₂Receptor-Induced CNS Neurogenesis in Adult Mice

Abstract

Neurogenesis continues in the adult forebrain subventricular zone (SVZ) and the dentate gyrus of the hippocampal formation. Degeneration of dopaminergic projections in Parkinson's disease and animals reduces, whereas ciliary neurotrophic factor (CNTF) promotes, neurogenesis. We tested whether the dopaminergic system promotes neurogenesis through CNTF. Astrocytes of the SVZ and dentate gyrus expressed CNTF and were close to dopaminergic terminals. Dopaminergic denervation in adult mice reduced CNTF mRNA by ϳ60%, whereas systemic treatment with the D 2 agonist quinpirole increased CNTF mRNA in the SVZ and hippocampal formation, and in cultured astrocytes by 1.5-5 fold. The effect of quinpirole in vitro was blocked by the D 2 antagonist eticlopride and did not cause astroglial proliferation or hypertrophy. Systemic quinpirole injections increased proliferation in wild-type mice by ϳ25-75% but not in CNTF

Dopaminergic modulation of neurogenesis in the subventricular zone of the adult brain

“…Indeed, D2 receptor activation has recently been shown to promote neurogenesis in the SVZ through a CNTF pathway. 41 Nevertheless a better understanding of the various factors that are involved in dopaminergic signalling in the SVZ and its effect on neurogenesis is important and this includes a knowledge of the dopamine agonist combination that maximally stimulates neuronal differentiation. Such knowledge will be crucial in the development of therapies designed to upregulate endogenous neurogenesis in order to produce increased numbers of newborn neurons to replace those lost in PD.…”

“…Dopamine causes eGF release by cleaving eGF from the eGF precursor, 16 which in turn stimulates eGFr enhancing proliferation. Other growth factors may also be involved in enhancing proliferation, e.g., CNtF 41 and also other unknown growth factors.…”

Stem cells of the adult mammalian brain and their niche

“…Consistently, experimental ablation of dopaminergic afferents results in reduced SEZ proliferation which is mainly attributable to TAPs [115,117,118]. Interestingly, recent evidence suggests that the dopamine induced increase in cell proliferation and neurogenesis in the adult SEZ is dependent on CNTF [119]. While dopamine signaling has been suggested to inhibit stem cell proliferation, whether aNSCs respond directly to dopamine signals needs to be elucidated.…”

From progenitors to integrated neurons: Role of neurotransmitters in adult olfactory neurogenesis

“…Moreover, dopamine can act directly on progenitor cells or indirectly inducing growth factor release, and drug treatment alone or coupled to specific surgical or pharmacological denervation could influence release of growth factors and in turn control cell proliferation. Indeed, besides the previously cited BDNF, dopamine-mediated effects on adult neurogenesis have been shown to involve ciliary neurotrophic factor (CNTF) (Yang et al, 2008). Dopaminergic denervation in adult mice reduces CNTF mRNA levels whereas systemic D2-like receptors agonist administration increases proliferation of neuronal progenitors in the SVZ of wild-type but not CNTF knock-out mice (Yang et al, 2008).…”

“…Indeed, besides the previously cited BDNF, dopamine-mediated effects on adult neurogenesis have been shown to involve ciliary neurotrophic factor (CNTF) (Yang et al, 2008). Dopaminergic denervation in adult mice reduces CNTF mRNA levels whereas systemic D2-like receptors agonist administration increases proliferation of neuronal progenitors in the SVZ of wild-type but not CNTF knock-out mice (Yang et al, 2008). CNTF knock-out mice show reduced neurogenesis and nigro-striatal denervation does not affect SVZ proliferation (Yang et al, 2008), suggesting that the dopaminergic innervation may regulate neurogenesis through CNTF.…”