Abstract
The elongation factor 2 kinase (eEF2K), likewise known as CaMKIII, has been demonstrated to be involved in antidepressant responses of NMDA receptor antagonists. Even so, it remains open whether direct inhibition of eEF2K without altering up-stream or other signaling pathways affects hippocampal synaptic transmission and neuronal network synchrony. Inhibition of eEF2K by the selective and potent eEF2K inhibitor A-484954 induced a fast pre-synaptically mediated enhancement of synaptic transmission and synchronization of neural network activity. The eEF2K-inhibition mediated potentiation of synaptic transmission of hippocampal CA1 neurons is most notably independent of protein synthesis and does not rely on protein kinase C, protein kinase A or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase 1/2. Moreover, the strengthening of synaptic transmission in the response to the inhibition of eEF2K was strongly attenuated by the inhibition of p38 MAPK. In addition, we show the involvement of barium-sensitive and more specific the TWIK-related potassium-1 (TREK-1) channels in the eEF2K-inhibition mediated potentiation of synaptic transmission. These findings reveal a novel pathway of eEF2K mediated regulation of hippocampal synaptic transmission. Further research is required to study whether such compounds could be beneficial for the development of mood disorder treatments with a fast-acting antidepressant response.
Highlights
Neuronal network activity alteration can be encoded by regulation of a large population of synapses, which is known as an important mechanism for the determination of the resting state of brain activity and for balancing learning-mediated changes in synaptic transmission
It was shown that a NMDA receptor blockade by ketamine led to an inhibition of eEF2K followed by enhanced protein synthesis and potentiation of hippocampal synapses that might mediate the antidepressant response of this compound (Autry et al, 2011; Duman et al, 2012; Dwyer and Duman, 2013; Monteggia et al, 2013)
The antidepressant effect of this derivative was still accompanied by a decrease in the phosphorylation of eEF2, an increase of synaptic transmission and neuronal network synchrony (Malinow, 2016; Zanos et al, 2016). eEF2K, known as CaMKIII, belongs to the atypical alpha-kinase family (Ryazanov et al, 1997; Middelbeek et al, 2010) and one of its substrate – the eEF2 – has been linked to the regulation of protein synthesis (Taha et al, 2013), and other substrates of eEF2K has been identified with potentially different outcome (Newman et al, 2013; Hu et al, 2014)
Summary
Neuronal network activity alteration can be encoded by regulation of a large population of synapses, which is known as an important mechanism for the determination of the resting state of brain activity and for balancing learning-mediated changes in synaptic transmission. It was shown that a NMDA receptor blockade by ketamine led to an inhibition of eEF2K followed by enhanced protein synthesis and potentiation of hippocampal synapses that might mediate the antidepressant response of this compound (Autry et al, 2011; Duman et al, 2012; Dwyer and Duman, 2013; Monteggia et al, 2013). The eEF2K itself underlies a complex dependency by upstream signaling pathways that results to a differently regulated eEF2K under various conditions and neuronal preparations (Kenney et al, 2014). It remains, unknown whether a specific eEF2K inhibition without modulation of up-stream or other signaling pathways is sufficient to alter synaptic transmission. We aimed to study the effects of direct eEF2K inhibition of hippocampal synaptic transmission and neuronal network activity in hippocampal slices and cultures
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