Potentiation of Schaffer-Collateral CA1 Synaptic Transmission by eEF2K and p38 MAPK Mediated Mechanisms

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.

Direct Medial Entorhinal Cortex Input to Hippocampal CA3 Is Crucial for eEF2K Inhibitor-Induced Neuronal Oscillations in the Mouse Hippocampus

“…It has been shown that A484954, a compound that inhibits eEF2K activity, induces slow-onset potentiation of hippocampal synaptic transmission (Weng et al, 2016). Here, we presented additional data showing that A484954 evokes a synchronized activity of neurons within the hippocampus and entorhinal cortex in acute hippocampal-entorhinal slices.…”

“…As introduced before, the eEF2K inhibitor A484954 increases synaptic transmission in acute hippocampal slices and induces neuronal network synchronization in primary hippocampal cultures (Weng et al, 2016). To further detail the A484954 effect on neuronal network activity in a more complex environment, experiments were conducted in hippocampal-entorhinal acute slices.…”

“…Acute hippocampal slices were prepared from 4-to 8-week-old male mice as described previously (Huang et al, 2015;Weng et al, 2016;Wang et al, 2017;Yun et al, 2018;Li et al, 2019) with slight modifications to ensure the connectivity of the hippocampal formation with the entorhinal cortex in vitro according to Xiong et al (2017). Briefly, after anesthesia with isoflurane, the brains were isolated and immersed in pre-carbogenated (95% O 2 /5% CO 2 ) ice-cold slicing salt buffer solution (composition in mM: 92 NaCl, 2.5 KCl, 0.5 CaCl 2 •2H 2 O, 10 MgSO 4 , 1.25 NaH 2 PO 4 , 25 glucose, 30 NaHCO 3 , 3 sodium pyruvate, 20 HEPES, titrated to pH 7.4; Pan et al, 2015).…”

“…In our previous work, we have shown that an eEF2K inhibitor induces the potentiation of hippocampal synaptic transmission and synchronizes the network activity of neurons in primary hippocampal cell cultures (Weng et al, 2016). However, it had not been studied whether such synchronization also takes place in interconnected hippocampal-entorhinal acute slices.…”

“…Some studies have found that eEF2K can effectively regulate the synaptic transmission of γ-aminobutyric acid (GABA), affect the excitation/inhibition balance of neurons, and therefore regulate cerebral oscillation (Heise et al, 2017). Another study described that specific inhibition of eEF2K in primary hippocampal cell cultures causes irregular neuronal activity to become synchronized (Weng et al, 2016). Moreover, the maintenance of hippocampal long-term plasticity depends under many conditions upon protein synthesis (Frey et al, 1988;Ris et al, 2009).…”