BAD and KATP channels regulate neuron excitability and epileptiform activity
Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensi...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/32721 |
| _version_ | 1811201672950579200 |
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| author | Juan Ramón Martínez-François María Carmen Fernández-Agüera Nidhi Nathwani Carolina Lahmann Veronica L Burnham Nika N Danial Gary Yellen |
| author_facet | Juan Ramón Martínez-François María Carmen Fernández-Agüera Nidhi Nathwani Carolina Lahmann Veronica L Burnham Nika N Danial Gary Yellen |
| author_sort | Juan Ramón Martínez-François |
| collection | DOAJ |
| description | Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (KATP) channels. Here we investigated the effect of BAD manipulation on KATP channel activity and excitability in acute brain slices. We found that BAD’s influence on neuronal KATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal KATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of KATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a ‘dentate gate’ function that is reinforced by increased KATP channel activity. |
| first_indexed | 2024-04-12T02:25:07Z |
| format | Article |
| id | doaj.art-0354aff8c3874c26813144fda6366778 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:25:07Z |
| publishDate | 2018-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0354aff8c3874c26813144fda63667782022-12-22T03:52:01ZengeLife Sciences Publications LtdeLife2050-084X2018-01-01710.7554/eLife.32721BAD and KATP channels regulate neuron excitability and epileptiform activityJuan Ramón Martínez-François0https://orcid.org/0000-0002-1035-2574María Carmen Fernández-Agüera1https://orcid.org/0000-0002-0769-213XNidhi Nathwani2Carolina Lahmann3Veronica L Burnham4Nika N Danial5Gary Yellen6https://orcid.org/0000-0003-4228-7866Department of Neurobiology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, United StatesDepartment of Neurobiology, Harvard Medical School, Boston, United StatesDepartment of Neurobiology, Harvard Medical School, Boston, United StatesDepartment of Neurobiology, Harvard Medical School, Boston, United StatesDepartment of Neurobiology, Harvard Medical School, Boston, United States; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United StatesDepartment of Neurobiology, Harvard Medical School, Boston, United StatesBrain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (KATP) channels. Here we investigated the effect of BAD manipulation on KATP channel activity and excitability in acute brain slices. We found that BAD’s influence on neuronal KATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal KATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of KATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a ‘dentate gate’ function that is reinforced by increased KATP channel activity.https://elifesciences.org/articles/32721EpilepsyCalcium imagingBrain sliceMetabolic seizure resistance |
| spellingShingle | Juan Ramón Martínez-François María Carmen Fernández-Agüera Nidhi Nathwani Carolina Lahmann Veronica L Burnham Nika N Danial Gary Yellen BAD and KATP channels regulate neuron excitability and epileptiform activity eLife Epilepsy Calcium imaging Brain slice Metabolic seizure resistance |
| title | BAD and KATP channels regulate neuron excitability and epileptiform activity |
| title_full | BAD and KATP channels regulate neuron excitability and epileptiform activity |
| title_fullStr | BAD and KATP channels regulate neuron excitability and epileptiform activity |
| title_full_unstemmed | BAD and KATP channels regulate neuron excitability and epileptiform activity |
| title_short | BAD and KATP channels regulate neuron excitability and epileptiform activity |
| title_sort | bad and katp channels regulate neuron excitability and epileptiform activity |
| topic | Epilepsy Calcium imaging Brain slice Metabolic seizure resistance |
| url | https://elifesciences.org/articles/32721 |
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