Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons

Abstract

Synaptic actions of brain-derived neurotrophic factor (BDNF) are 'gated' by cyclic AMP (cAMP), but the underlying molecular mechanisms remain unclear. Here we report that cAMP regulates BDNF function in mature hippocampal neurons by modulating the signaling and trafficking of its receptor TrkB. cAMP gated the TrkB tyrosine kinase with three characteristic features: BDNF-induced TrkB phosphorylation was attenuated by inhibitors of cAMP signaling, it was potentiated by cAMP analogs, and activation of the cAMP pathway alone had no effect. In addition, cAMP facilitated trafficking of TrkB to dendritic spines, possibly by promoting its interaction with synaptic scaffolding protein PSD-95. Norepinephrinergic and dopaminergic agonists, which elevate intracellular cAMP concentration, also enhanced TrkB phosphorylation and its translocation to spines. cAMP gated long-term modulation by BDNF of spine density, but not the number of primary dendrites. These results reveal a specific role of cAMP in controlling BDNF actions in the brain, and provide new insights into the molecular mechanism underlying cAMP gating.

Adenosine A1 receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro

“…Primary rat cortical neuronal cultures Dissociated primary cultures of cortical neurons from embryonic day 18 (E18) rats were prepared from timed-pregnant Sprague-Dawley rats as described previously with minor modifications [12] . Fetuses were removed under sterile conditions and kept in iced D-Hanks' solution for the microscopic dissection of the cortex.…”

Pharmacologically Diverse Antidepressants Rapidly Activate Brain-Derived Neurotrophic Factor Receptor TrkB and Induce Phospholipase-Cγ Signaling Pathways in Mouse Brain

“…However, we cannot rule out the possibility that antidepressants increase TrkB signaling without influencing BDNF release. Increased intracellular cAMP or membrane depolarization have been shown to increase the membrane localization of TrkB thus enhancing the ability of BDNF to induce TrkB autophosphorylation (Meyer-Franke et al, 1998;Haapasalo et al, 2002;Du et al, 2003;Ji et al, 2005). Furthermore, some G-protein-coupled receptors have been shown to transactivate TrkB receptors independently of BDNF (Lee et al, 2002a;Lee et al, 2002b;Berghuis et al, 2005).…”

Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS

“…Thus, density, complexity and the number of spine synapses is increased by both estrogen and BDNF in hippocampus. It is noteworthy, however, that the exact nature of the changes in morphology may;e distinct: some studies indicate that spine shape or length change whereas other studies report that spine synapses are affected [41,[59][60][61][62][63][64][65][66][67][68][69][70][71]. Such data provide some caution to the assumption that estradiol and BDNF have exactly the same effects.…”