BAD and KATP channels regulate neuron excitability and epileptiform activity

Martínez-François, Juan Ramón; Fernández-Agüera, María Carmen; Nathwani, Nidhi; Lahmann, Carolina; Burnham, Veronica L.; Danial, Nika N.; Yellen, Gary

doi:10.7554/elife.32721

Cited by 41 publications

(33 citation statements)

References 127 publications

(168 reference statements)

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“…This is somewhat lower as reported before based on estimates of [ATP] using the sensor ATeam1.03 (Toloe et al 2014). A reduction in this range might alter the conductance of K ATP channels, resulting in a dampening of neuronal excitability, thereby executing an anti-convulsant effect (Proks & Ashcroft, 2009;Mollajew et al 2013;Toloe et al 2014;Martinez-Francois et al 2018).…”

Section: Different Activity Patterns Neuronal Atp Levelsmentioning

confidence: 92%

“…Unsurprisingly, former work established a direct link between cellular energy metabolism, NKA activity and Na + regulation, demonstrating that metabolic failure results both in large shifts in neuronal [Na + ] i and a substantial decrease in intracellular ATP concentrations ([ATP] i ) with secondary breakdown of other ion gradients and detrimental consequences (Hansen, 1985;Erecinska & Silver, 1994;Leng et al 2014;Gerkau et al 2017). In addition to ATP-dependent ion transporters, many neurons express K ATP channels that couple their metabolic state to their excitability and which are activated by a more moderate decline in cellular [ATP] (Proks & Ashcroft, 2009;Tanner et al 2011;Mollajew et al 2013;Martinez-Francois et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Gerkau

Lerchundi

Nelson

et al. 2019

The Journal of Physiology

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Key points Employing quantitative Na+‐imaging and Förster resonance energy transfer‐based imaging with ATeam1.03YEMK (ATeam), we studied the relation between activity‐induced Na+ influx and intracellular ATP in CA1 pyramidal neurons of the mouse hippocampus. Calibration of ATeam in situ enabled a quantitative estimate of changes in intracellular ATP concentrations. Different paradigms of stimulation that induced global Na+ influx into the entire neuron resulted in decreases in [ATP] in the range of 0.1–0.6 mm in somata and dendrites, while Na+ influx that was locally restricted to parts of dendrites did not evoke a detectable change in dendritic [ATP]. Our data suggest that global Na+ transients require global cellular activation of the Na+/K+‐ATPase resulting in a consumption of ATP that transiently overrides its production. For recovery from locally restricted Na+ influx, ATP production as well as fast intracellular diffusion of ATP and Na+ might prevent a local drop in [ATP]. Abstract Excitatory neuronal activity results in the influx of Na+ through voltage‐ and ligand‐gated channels. Recovery from accompanying increases in intracellular Na+ concentrations ([Na+]i) is mainly mediated by the Na+/K+‐ATPase (NKA) and is one of the major energy‐consuming processes in the brain. Here, we analysed the relation between different patterns of activity‐induced [Na+]i signalling and ATP in mouse hippocampal CA1 pyramidal neurons by Na+ imaging with sodium‐binding benzofurane isophthalate (SBFI) and employing the genetically encoded nanosensor ATeam1.03YEMK (ATeam). In situ calibrations demonstrated a sigmoidal dependence of the ATeam Förster resonance energy transfer ratio on the intracellular ATP concentration ([ATP]i) with an apparent KD of 2.6 mm, indicating its suitability for [ATP]i measurement. Induction of recurrent network activity resulted in global [Na+]i oscillations with amplitudes of ∼10 mm, encompassing somata and dendrites. These were accompanied by a steady decline in [ATP]i by 0.3–0.4 mm in both compartments. Global [Na+]i transients, induced by afferent fibre stimulation or bath application of glutamate, caused delayed, transient decreases in [ATP]i as well. Brief focal glutamate application that evoked transient local Na+ influx into a dendrite, however, did not result in a measurable reduction in [ATP]i. Our results suggest that ATP consumption by the NKA following global [Na+]i transients temporarily overrides its availability, causing a decrease in [ATP]i. Locally restricted Na+ transients, however, do not result in detectable changes in local [ATP]i, suggesting that ATP production, together with rapid intracellular diffusion of both ATP and Na+ from and to unstimulated neighbouring regions, counteracts a local energy shortage under these conditions.

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Section: Different Activity Patterns Neuronal Atp Levelsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Gerkau

Lerchundi

Nelson

et al. 2019

The Journal of Physiology

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“…Studies on brain energy metabolism have focused mainly on broad aspects. This includes the energy budget of excitatory neuronal signaling (Attwell and Laughlin, 2001;Lutas and Yellen, 2013;Martinez-Francois et al, 2018), the favorable energy substrate for neurons (Chih et al, 2001;Díaz-García et al, 2017;Diaz-Garcia and Yellen, 2019;Erecińska and Silver, 2001), and the contributions of glycolysis and oxidative phosphorylation to ATP generation (Yellen, 2018).…”

Section: Neuroenergetics Of Neuronal Ensemblesmentioning

confidence: 99%

Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations

Elzoheiry

Lewen

Schneider

et al. 2019

J Cereb Blood Flow Metab

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Disturbances of cognitive functions occur rapidly during acute metabolic stress. However, the underlying mechanisms are not fully understood. Cortical gamma oscillations (30–100 Hz) emerging from precise synaptic transmission between excitatory principal neurons and inhibitory interneurons, such as fast-spiking GABAergic basket cells, are associated with higher brain functions, like sensory perception, selective attention and memory formation. We investigated the alterations of cholinergic gamma oscillations at the level of neuronal ensembles in the CA3 region of rat hippocampal slice cultures. We combined electrophysiology, calcium imaging (CamKII.GCaMP6f) and mild metabolic stress that was induced by rotenone, a lipophilic and highly selective inhibitor of complex I in the respiratory chain of mitochondria. The detected pyramidal cell ensembles showing repetitive patterns of activity were highly sensitive to mild metabolic stress. Whereas such synchronised multicellular activity diminished, the overall activity of individual pyramidal cells was unaffected. Additionally, mild metabolic stress had no effect on the rate of action potential generation in fast-spiking neural units. However, the partial disinhibition of slow-spiking neural units suggests that disturbances of ensemble formation likely result from alterations in synaptic inhibition. Our study bridges disturbances on the (multi-)cellular and network level to putative cognitive impairment on the system level.

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“…From the viewpoint of electrical control, the antiseizure effects of the BAD knockout are mediated by K ATP channels (Giménez-Cassina et al, 2012 ; Martínez-François et al, 2018 ). K ATP channel currents in hippocampal neurons were shown to become larger in BAD-knockout mice, which was blocked by the genetic ablation of Kir6.2 (a pore-forming subunit of K ATP channels) or K ATP channel blockers (Giménez-Cassina et al, 2012 ).…”

Section: Molecules For Electrical Control By the Ketogenic Dietmentioning

confidence: 99%

Electrical Control in Neurons by the Ketogenic Diet

Sada

Inoue

2018

Front. Cell. Neurosci.

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The ketogenic diet is used as a diet treatment for drug-resistant epilepsy, but there are no antiepileptic drugs based on the ketogenic diet. The ketogenic diet changes energy metabolites (ketone bodies, glucose and lactate) in the brain, which consequently changes electrical activities in neurons and ultimately suppresses seizures in epileptic patients. In order to elucidate the antiseizure effects of the ketogenic diet, it is important to clarify the mechanism by which these metabolic changes are converted to electrical changes in neurons. In this review, we summarize electrophysiological studies focusing on electrical control in neurons by the ketogenic diet. Recent studies have identified electrical regulators driven by the ketogenic diet: ion channels (ATP-sensitive K+ channels and voltage-dependent Ca2+ channels), synaptic receptors (AMPA-type glutamate receptors and adenosine A1 receptors), neurotransmitter transporters (vesicular glutamate transporters), and others (BCL-2-associated agonist of cell death and lactate dehydrogenase). Thus, the ketogenic diet presumably elicits neuronal inhibition via the combined actions of these molecules. From the viewpoint of drug development, these molecules are valuable as targets for the development of new antiepileptic drugs. Drug therapy to mimic the ketogenic diet may be feasible in the future, through the combination of multiple antiepileptic drugs targeting these molecules.

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BAD and KATP channels regulate neuron excitability and epileptiform activity

Cited by 41 publications

References 127 publications

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations

Electrical Control in Neurons by the Ketogenic Diet

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