You are here

| Neural Stem Cells

Adenosinergic Signaling and BDNF Combine to Control Hippocampal Neurogenesis

Review of “Regulation of hippocampal postnatal and adult neurogenesis by adenosine A2A receptor: Interaction with brain-derived neurotrophic factor” from STEM CELLS by Stuart P. Atkinson

Functioning through the high affinity G-protein-coupled A2A receptor (A2AR) subtype, adenosine regulates critical neuronal functions that include regulating brain development [1] and neuronal plasticity [2]. Interestingly, recent research has suggested that A2ARs also play crucial roles during postnatal neurogenesis [3, 4] and control the facilitatory fast actions of brain-derived neurotrophic factor (BDNF) at hippocampal synapses, with consequences for synaptic transmission and plasticity [5-8].

With this knowledge in hand, researchers led by Sara Xapelli (Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal) sought to fully explore the A2AR-mediated regulation of BDNF-mediated actions during adult neurogenesis. The results of this study, reported recently in STEM CELLS, broaden our appreciation of adenosinergic signaling in the brain and may support the development of novel brain repair strategies for a range of pathological conditions [9].

Ribeiro et al. discovered that activation of A2ARs in postnatal rat dentate gyrus-neurosphere cultures and six-week-old rats via treatment with a selective agonist enhanced hippocampal neurogenesis, as evidenced by the increased self-renewal and differentiation of neural stem/progenitor cells and production of newborn neurons and the reduced level of neural apoptosis. Overall, these outcomes contributed to the appearance of a higher density of immature and mature neuronal cells and glutamatergic neurons, in particular. Furthermore, the authors established that A2AR activation prompted BDNF secretion and that the BDNF-mediated increase in cell proliferation and neuronal differentiation (but not self-renewal) required the endogenous activation of A2AR.

While these findings suggest a tight interplay between BDNF and A2AR, future studies will be required to reveal the precise nature of this interaction. Furthermore, the authors hope to explore the potential relevance of adenosinergic signaling on learning and memory formation and the possible application of this knowledge to neuronal repair and regeneration.

For more on how adenosinergic signaling and BDNF combine to control hippocampal neurogenesis, stay tuned to the Stem Cells Portal!


  1. Ribeiro FF, Neves-Tome R, Assaife-Lopes N, et al., Axonal elongation and dendritic branching is enhanced by adenosine A2A receptors activation in cerebral cortical neurons. Brain Struct Funct 2016;221:2777-99.
  2. Dias RB, Rombo DM, Ribeiro JA, et al., Adenosine: setting the stage for plasticity. Trends Neurosci 2013;36:248-57.
  3. Maraula G, Traini C, Mello T, et al., Effects of oxygen and glucose deprivation on synaptic transmission in rat dentate gyrus: role of A2A adenosine receptors. Neuropharmacology 2013;67:511-20.
  4. Moscoso-Castro M, Lopez-Cano M, Gracia-Rubio I, et al., Cognitive impairments associated with alterations in synaptic proteins induced by the genetic loss of adenosine A2A receptors in mice. Neuropharmacology 2017;126:48-57.
  5. Vaz SH, Lerias SR, Parreira S, et al., Adenosine A2A receptor activation is determinant for BDNF actions upon GABA and glutamate release from rat hippocampal synaptosomes. Purinergic Signal 2015;11:607-12.
  6. Rodrigues TM, Jeronimo-Santos A, Sebastiao AM, et al., Adenosine A(2A) Receptors as novel upstream regulators of BDNF-mediated attenuation of hippocampal Long-Term Depression (LTD). Neuropharmacology 2014;79:389-98.
  7. Fontinha BM, Diogenes MJ, Ribeiro JA, et al., Enhancement of long-term potentiation by brain-derived neurotrophic factor requires adenosine A2A receptor activation by endogenous adenosine. Neuropharmacology 2008;54:924-33.
  8. Diogenes MJ, Fernandes CC, Sebastiao AM, et al., Activation of adenosine A2A receptor facilitates brain-derived neurotrophic factor modulation of synaptic transmission in hippocampal slices. J Neurosci 2004;24:2905-13.
  9. Ribeiro FF, Ferreira F, Rodrigues RS, et al., Regulation of hippocampal postnatal and adult neurogenesis by adenosine A2A receptor: Interaction with brain-derived neurotrophic factor. STEM CELLS 2021;39:1362-1381.