Axonal elongation and dendritic branching is enhanced by adenosine A2A receptors activation in cerebral cortical neurons

Abstract

Axon growth and dendrite development are key processes for the establishment of a functional neuronal network. Adenosine, which is released by neurons and glia, is a known modulator of synaptic transmission but its influence over neuronal growth has been much less investigated. We now explored the action of adenosine A2A receptors (A2AR) upon neurite outgrowth, discriminating actions over the axon or dendrites, and the mechanisms involved. Morphometric analysis of primary cultures of cortical neurons from E18 Sprague-Dawley rats demonstrated that an A2AR agonist, CGS 21680, enhances axonal elongation and dendritic branching, being the former prevented by inhibitors of phosphoinositide 3-kinase, mitogen-activated protein kinase and phospholipase C, but not of protein kinase A. By testing the influence of a scavenger of BDNF (brain-derived neurotrophic factor) over the action of the A2AR agonist and the action of a selective A2AR antagonist over the action of BDNF, we could conclude that while the action of A2ARs upon dendritic branching is dependent on the presence of endogenous BDNF, the influence of A2ARs upon axonal elongation is independent of endogenous BDNF. In consonance with the action over axonal elongation, A2AR activation promoted a decrease in microtubule stability and an increase in microtubule growth speed in axonal growth cones. In conclusion, we disclose a facilitatory action of A2ARs upon axonal elongation and microtubule dynamics, providing new insights for A2ARs regulation of neuronal differentiation and axonal regeneration.

BDNF Signaling Promotes Vestibular Compensation by Increasing Neurogenesis and Remodeling the Expression of Potassium-Chloride Cotransporter KCC2 and GABAAReceptor in the Vestibular Nuclei

“…More specifically, we observed that newborn GABAergic neurons exhibited both smaller soma and dendritic fields in K252a-treated animals, whereas these cells exhibited a larger soma surface with enhanced dendritic branching in the UVN-BDNF group. Axon growth and dendrite development are key processes for the establishment of a functional neuronal network and it was reported recently that dendritic branching is BDNF dependent (Ribeiro et al, 2015). Together, our results demonstrate that BDNF action through TrkB receptors amplifies cell proliferation, survival, and development of functional dendritic branching in the deafferented VN of the vestibular-lesioned cats.…”

“…Here, we show that continuous BDNF administration into the fourth ventricle after UVN significantly increases the production of newly generated cells, confirming the proneurogenic properties of this growth factor in vivo. Similarly, a previous study showed that BDNF infusion into the lateral ventricle of the adult rat leads to new neurons in the striatum, septum, thalamus, and hypothalamus (Pencea et al, 2001). Next, we used K252a and showed that it strongly attenuated the proneurogenic action of UVN.…”

“…In the present study, we confirmed this result and also show that, 30 d after lesion, BDNF infusion potentiated this effect. Likewise, it has been described that BDNF enhances acetylcholine release (Auld et al, 2001) and promotes a cholinergic phenotype in basal forebrain neurons (Nonner et al, 2000) through a TrkB-dependent mechanism (Burgess and Aubert, 2006). Interestingly, ACh agonists and acetylcholinesterase inhibitors have also been found to increase the firing activity of VN neurons in vitro and in vivo through muscarinic and nicotinic receptors (Yamamoto, 1967;Ujihara et al, 1989;Phelan and Gallagher, 1992).…”

“…Completeness of vestibular nerve section had been assessed by histological procedures in previous studies (Lacour et al, 1976). For the implantation and use of osmotic minipumps containing saline, BDNF, or TrK antagonist (K252a), concentrations of BDNF and K252a were selected with reference to studies showing the effect of in vivo infusion of BDNF on neurogenesis (Pencea et al, 2001) and vestibular compensation (Maingay et al, 2000). K252a is a BDNF antagonist that has a high affinity for the TrkB receptor and belongs to the K252 family of alkaloid toxins, which are protein kinase inhibitors.…”

“…Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of proteins, has been shown to promote neurite outgrowth, cell survival, differentiation, migration, and activity-dependent neuroplasticity in the CNS and peripheral nervous system (Greenberg et al, 2009;Park and Poo, 2013). In the context of adult hippocampal neurogenesis, BDNF is known to influence neuronal activity through GABA-mediated effects (Lee et al, 2002;Sairanen et al, 2005;Bergami et al, 2008;Waterhouse et al, 2012).…”