Adenosine A1 receptor inhibits postnatal neurogenesis and sustains astrogliogenesis from the subventricular zone

Abstract

We previously demonstrated that activation of ATP P2X receptors during oxygen and glucose deprivation inhibits neuroblast migration and in vitro neurogenesis from the subventricular zone (SVZ). Here, we have studied the effects of adenosine, the natural end-product of ATP hydrolysis, in modulating neurogenesis and gliogenesis from the SVZ. We provide immunochemical, molecular and pharmacological evidence that adenosine via A1 receptors reduces neuronal differentiation of neurosphere cultures generated from postnatal SVZ. Furthermore, activation of A1 receptors induces downregulation of genes related to neurogenesis as demonstrated by gene expression analysis. Specifically, we found that A1 receptors trigger a signaling cascade that, through the release of IL10, turns on the Bmp2/SMAD pathway. Furthermore, activating A1 receptors in SVZ-neural progenitor cells inhibits neurogenesis and stimulates astrogliogenesis as assayed in vitro in neurosphere cultures and in vivo in the olfactory bulb. Together, these data indicate that adenosine acting at A1 receptors negatively regulates adult neurogenesis while promoting astrogliogenesis, and that this feature may be relevant to pathological conditions whereby purines are profusely released. GLIA 2016;64:1465-1478.

Effects of FTY720 on brain neurogenic niches in vitro and after kainic acid-induced injury

“…Postnatal and adult NSCs could have different differentiation potentials, although a recent study in vitro reported a similar behaviour of postnatal (p7) and adult (p42)-derived NSCs [28]. Despite this consideration, we decided to use adult animals for the in vivo protocol as the main aim of our study was to examine the response of neurogenic niches to FTY720 after injury.…”

“…NSC cultures were prepared from 4 to 7-day-old Sprague-Dawley rat pups, as previously described [27, 28], with slight modifications. Briefly, the SVZ was isolated and minced with a McIlwain tissue chopper.…”

Neurogenesis and Gliogenesis: Relevance of Adenosine for Neuroregeneration in Brain Disorders

“…In fact, these few studies only report the expression of A 1 Rs, A 2A Rs, A 2B Rs, and A 3 Rs in NSCs isolated from adult mice SVZ. [52][53][54] Expression in DG NSCs has not been shown yet.…”

“…53,55 Of interest, a recent study evaluating adenosine actions on SVZ demonstrates that adenosine, through A 1 Rs, reduces neuronal differentiation, correlating with a downregulation of proneurogenic genes. 54 Regarding A 2A R-mediated modulation of postnatal neurogenesis, A 2A R activation has been shown to inhibit primary SVZ-derived neurosphere proliferation. 52 Oliveros et al observed that the pharmacological blockade of A 2A R promoted impulsive behavior, and that in these conditions there was a potentiation of neuroblast proliferation, and likely of adult neurogenesis, in the dorsal hippocampus.…”

Nuclear factor‐kappaB regulates multiple steps of gliogenesis in the developing murine cerebral cortex

“…Toward the end of the neurogenic phase, at approximately gestation day 17 in the mouse embryo, neocortical radial glia undergo a transition from a neurogenic to a gliogenic mode (“gliogenic switch”) and acquire gliogenic competence (Benito‐Muñoz, Matute, & Cavaliere, ; Li et al, ; Paridaen & Huttner, 2014; Rowitch & Kriegstein, ). During this transition, neurogenic genes are repressed and progliogenic genes are derepressed or activated through a variety of mechanisms, thereby allowing NPCs to respond to intrinsic and extrinsic progliogenic signals leading to the activation of specific glial cell lineage differentiation programs, ultimately resulting in the generation of cortical astrocytes and oligodendrocytes (Bayraktar, Fuentealba, Alvarez‐Buylla, & Rowitch, ; Ge & Jia, ; Li et al, ; Molofsky & Deneen, ; Rowitch & Kriegstein, ).…”