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. 2019 Aug 13;13:368. doi: 10.3389/fncel.2019.00368

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Copyright © 2019 Pradhan, Noakes and Bellingham.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Schematic figure representing activity-dependent interplay between glutamate-induced excitotoxicity and BDNF-TrkB signaling. The arrival of action potential (step 1), triggers the influx of Ca²⁺ ions into pre-synaptic terminal (step 2), the rise in intracellular calcium (step 3) in turn triggers the fusion of synaptic vesicles with pre-synaptic membrane to release glutamate (light purple dots) from the terminal (step 4). Membrane depolarization also results in BDNF secretion (orange dots) (step 4) and release pre-synaptically into the synaptic cleft. Dysfunctional glutamate transporters (EAAT2) in ALS results in retention of excessive glutamate in the synaptic cleft (step 5). Post-synaptically, Ca²⁺ enters through voltage gated calcium channels and via calcium-permeable glutamate receptors (NMDA, green; AMPA magenta; step 6). BDNF binding to TrkB alters the neuronal excitability of ion channels and also enhances post-synaptic glutamate receptor activation causing influx Ca²⁺ of ions post-synaptically (step 7). Excessive glutamate in the synaptic-cleft over-activates its receptors increasing the intracellular Ca²⁺ furthermore (step 8). Impaired Na⁺/Ca²⁺ exchanger and ATP pumps in SOD1^G93A mice results in enhanced Ca²⁺ intracellularly (DeJesus-Hernandez et al., 2011; Sirabella et al., 2018). Ca²⁺ released from the intracellular store adds to the Ca²⁺ concentration (step 8). Enhanced Ca²⁺ in the post-synaptic neuron also triggers increased Ca²⁺ dependent secretion and release of BDNF extracellularly causing enhanced BDNF extracellularly (step 9). Trans-activation of TrkB by A₂_aRs also triggers calcium dependent signaling, activating adenylyl cyclase and leading to increased cAMP and PKA phosphorylation, which in turn influences BDNF secretion (step 10). This increased BDNF in the synaptic cleft binds to its receptors TrkB and repeats the process of Ca²⁺ influx and modulation of glutamate receptors, eventually leading to Ca²⁺ overload (step 11) making the neurons hyper-excitable (step 12) which eventually leads to neuronal death (step 13).