TREK-1 Null Impairs Neuronal Excitability, Synaptic Plasticity, and Cognitive Function

Wang, Wei; Kiyoshi, Conrad M.; Du, Yixing; Taylor, Anne; Sheehan, Erica R; Wu, Xiao; Zhou, Min

doi:10.1007/s12035-019-01828-x

Cited by 19 publications

(12 citation statements)

References 45 publications

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“…In voltage-clamp recording, the depolarization steps induced a sequential activation of voltage-gated inward Na + (IN a ), outward transient K + channels (IK a ) and delayed rectifying K + channels (IK d ) ( Figure 1B). These properties were consistent with our previous reports [29,31,32].…”

Section: Induction Of Neuronal Epileptiform Discharges In Hippocampalsupporting

confidence: 94%

“…In current-clamp recording, the CA1 pyramidal neurons were quiescent at resting conditions. The action potentials could only be induced by positive current injection, and the induced multiple spikes exhibited a characteristic adaptation ( Figure 1C) [31,32]. Upon exposure to Mg 2+ free-PTX solution, epileptiform discharges (EDs) at variable durations were induced ( Figure 1D) at the frequency of 4.0 ± 0.8/min (n = 5 recordings from three mice, p < 0.01).…”

Section: Induction Of Neuronal Epileptiform Discharges In Hippocampalmentioning

confidence: 97%

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Epileptiform Neuronal Discharges Impair Astrocyte Syncytial Isopotentiality in Acute Hippocampal Slices

Wang

Aten

et al. 2020

Brain Sciences

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Astrocyte syncytial isopotentiality is a physiological mechanism resulting from a strong electrical coupling among astrocytes. We have previously shown that syncytial isopotentiality exists as a system-wide feature that coordinates astrocytes into a system for high efficient regulation of brain homeostasis. Neuronal activity is known to regulate gap junction coupling through alteration of extracellular ions and neurotransmitters. However, the extent to which epileptic neuronal activity impairs the syncytial isopotentiality is unknown. Here, the neuronal epileptiform bursts were induced in acute hippocampal slices by removal of Mg2+ (Mg2+ free) from bath solution and inhibition of γ-aminobutyric acid A (GABAA) receptors by 100 µM picrotoxin (PTX). The change in syncytial coupling was monitored by using a K+ free-Na+-containing electrode solution ([Na+]p) in the electrophysiological recording where the substitution of intracellular K+ by Na+ ions dissipates the physiological membrane potential (VM) to ~0 mV in the recorded astrocyte. However, in a syncytial coupled astrocyte, the [Na+]p induced VM loss can be compensated by the coupled astrocytes to a quasi-physiological membrane potential of ~73 mV. After short-term exposure to this experimental epileptic condition, a significant closure of syncytial coupling was indicated by a shift of the quasi-physiological membrane potential to −60 mV, corresponding to a 90% reduction of syncytial coupling strength. Consequently, the closure of syncytial coupling significantly decreased the ability of the syncytium for spatial redistribution of K+ ions. Altogether, our results show that epileptiform neuronal discharges weaken the strength of syncytial coupling and that in turn impairs the capacity of a syncytium for spatial redistribution of K+ ions.

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Section: Induction Of Neuronal Epileptiform Discharges In Hippocampalsupporting

confidence: 94%

Section: Induction Of Neuronal Epileptiform Discharges In Hippocampalmentioning

confidence: 97%

Epileptiform Neuronal Discharges Impair Astrocyte Syncytial Isopotentiality in Acute Hippocampal Slices

Wang

Aten

et al. 2020

Brain Sciences

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“…In neurons, TREK-1 plays a crucial role in the maintenance of the resting membrane potential and thereby neuronal excitability (Enyedi and Czirjak, 2010; POPDC1 and synaptic plasticity 2 1 Honoré 2007). Studies have also implicated TREK-1 in synaptic plasticity and memory (Cai et al 2017;Wang et al 2020;Weng et al 2016). However, we think that the POPDC1-TREK-1 interaction may not be important in hippocampal CA1 neurons because we observed no significant changes in basal synaptic transmission in the slices from Popdc1 KO mice as assessed by changes in input-output relation (Fig.…”

Section: Popdc1 and Synaptic Plasticity 1mentioning

confidence: 72%

Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity

Shetty

Ris

Schindler

et al. 2021

Preprint

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Extensive research has uncovered diverse forms of synaptic plasticity and a wide array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cAMP-dependent signaling pathways have been crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of POPDC1 (or BVES), a cAMP effector protein expressed in brain, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as PKA and EPAC, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains. These properties suggest that POPDC1 may have a unique role in cAMP-mediated signaling underlying synaptic plasticity. Our results show that POPDC1 is enriched in hippocampal synaptoneurosomes. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit enhanced long-term potentiation (LTP) induced by a variety of stimulation paradigms, particularly in response to weak stimulation paradigms that in slices from wildtype mice induce only transient LTP. Furthermore, Popdc1 KO mice did not display any further enhancement in forskolin-induced LTP observed following inhibition of phosphodiesterases (PDEs), suggesting a possible modulation of cAMP-PDE signaling by POPDC1. Taken together, these data reveal POPDC1 as a novel player in the regulation of hippocampal synaptic plasticity and as a potential target for cognitive enhancement strategies.

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“…TREK-1 can regulate the excitability of neurons, but its precise roles may depend on the type of neuron. In pyramidal neurons of the CA1 region of the hippocampus, TREK-1 deficiency depolarized resting neurons, reduced the rheobase, and increased action potential frequency [54]. Similarly, in serotonergic neurons of the dorsal raphe nucleus (DRN), TREK-1 knockout increased discharge frequency in mice [55].…”

Section: Treksmentioning

confidence: 99%

Contribution of Neuronal and Glial Two-Pore-Domain Potassium Channels in Health and Neurological Disorders

et al. 2021

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Two-pore-domain potassium (K2P) channels are widespread in the nervous system and play a critical role in maintaining membrane potential in neurons and glia. They have been implicated in many stress-relevant neurological disorders, including pain, sleep disorder, epilepsy, ischemia, and depression. K2P channels give rise to leaky K+ currents, which stabilize cellular membrane potential and regulate cellular excitability. A range of natural and chemical effectors, including temperature, pressure, pH, phospholipids, and intracellular signaling molecules, substantially modulate the activity of K2P channels. In this review, we summarize the contribution of K2P channels to neuronal excitability and to potassium homeostasis in glia. We describe recently discovered functions of K2P channels in glia, such as astrocytic passive conductance and glutamate release, microglial surveillance, and myelin generation by oligodendrocytes. We also discuss the potential role of glial K2P channels in neurological disorders. In the end, we discuss current limitations in K2P channel researches and suggest directions for future studies.

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TREK-1 Null Impairs Neuronal Excitability, Synaptic Plasticity, and Cognitive Function

Cited by 19 publications

References 45 publications

Epileptiform Neuronal Discharges Impair Astrocyte Syncytial Isopotentiality in Acute Hippocampal Slices

Epileptiform Neuronal Discharges Impair Astrocyte Syncytial Isopotentiality in Acute Hippocampal Slices

Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity

Contribution of Neuronal and Glial Two-Pore-Domain Potassium Channels in Health and Neurological Disorders

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