Figure 2.

DHA signaling pathways in neuron survival, morphology, and synaptic function. (A) DHA can promote neuron survival by different mechanisms, including the induction of cAMP response element-binding (CREB) and nuclear factor erythroid 2-related factor 2 (NRF2) pathways, or apoptosis inhibition by reducing the activities of caspase-3 and caspase-8. (B) Regarding neural morphology, DHA can trigger the activation of retinoid X receptor (RXR) and the G-protein coupled receptor GPR40/FFAR1, which can increase intracellular calcium by activation of Gq/PLC/IP3 or by activation of the tyrosine kinase Trk-B receptor (Trk-B-R) by its activator, brain-derived neurotrophic factor (BDNF), with subsequent activation of the CREB pathway. This latter axis can also be activated by the DHA metabolite DEA (synaptomide), which induces a GPR110-mediated increase in cAMP levels. (C) The effects of DHA and DEA on synaptic function include the expression of synaptic proteins, such as postsynaptic receptors or scaffolding proteins (left scheme), which lead to an enhancement of synaptic communication (middle scheme). Additionally, DHA exert a direct effect on ion channels, modulating their gating properties (right scheme). Whether DEA is also able to modulate the activity of ion channels is unknown.