KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels
Summary: KCC2 regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in numerous neurological and psychiatric disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-07-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719307594 |
| _version_ | 1818000761945063424 |
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| author | Marie Goutierre Sana Al Awabdh Florian Donneger Emeline François Daniel Gomez-Dominguez Theano Irinopoulou Liset Menendez de la Prida Jean Christophe Poncer |
| author_facet | Marie Goutierre Sana Al Awabdh Florian Donneger Emeline François Daniel Gomez-Dominguez Theano Irinopoulou Liset Menendez de la Prida Jean Christophe Poncer |
| author_sort | Marie Goutierre |
| collection | DOAJ |
| description | Summary: KCC2 regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in numerous neurological and psychiatric disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents is depolarized in KCC2 knockdown neurons, this shift is compensated by depolarization of the resting membrane potential. This reflects downregulation of leak potassium currents. We show KCC2 interacts with Task-3 (KCNK9) channels and is required for their membrane expression. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis, which could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that perturb network activity thus offering additional targets for therapeutic intervention. : Reduced KCC2 expression is associated with numerous neurological and psychiatric disorders and assumed to primarily affect GABA signaling. Goutierre et al. demonstrate chronic KCC2 knockdown in rat hippocampus has little effect on GABA signaling but affects neuronal excitability and network activity by downregulating membrane expression of Task-3 leak potassium channels. Keywords: KCC2, hippocampus, epilepsy, chloride, GABA, synaptic transmission, transporter, K2P, leak channels, dentate gyrus |
| first_indexed | 2024-04-14T03:25:51Z |
| format | Article |
| id | doaj.art-e639bdd041d9453db79f8a9062f7a422 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-14T03:25:51Z |
| publishDate | 2019-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-e639bdd041d9453db79f8a9062f7a4222022-12-22T02:15:11ZengElsevierCell Reports2211-12472019-07-0128191103.e7KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 ChannelsMarie Goutierre0Sana Al Awabdh1Florian Donneger2Emeline François3Daniel Gomez-Dominguez4Theano Irinopoulou5Liset Menendez de la Prida6Jean Christophe Poncer7INSERM UMR-S 1270, 75005 Paris, France; Sorbonne Université, 75005 Paris, France; Institut du Fer à Moulin, 75005 Paris, FranceINSERM UMR-S 1270, 75005 Paris, France; Sorbonne Université, 75005 Paris, France; Institut du Fer à Moulin, 75005 Paris, FranceINSERM UMR-S 1270, 75005 Paris, France; Sorbonne Université, 75005 Paris, France; Institut du Fer à Moulin, 75005 Paris, FranceINSERM UMR-S 1270, 75005 Paris, France; Sorbonne Université, 75005 Paris, France; Institut du Fer à Moulin, 75005 Paris, FranceInstituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid 28002, SpainINSERM UMR-S 1270, 75005 Paris, France; Sorbonne Université, 75005 Paris, France; Institut du Fer à Moulin, 75005 Paris, FranceInstituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid 28002, SpainINSERM UMR-S 1270, 75005 Paris, France; Sorbonne Université, 75005 Paris, France; Institut du Fer à Moulin, 75005 Paris, France; Corresponding authorSummary: KCC2 regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in numerous neurological and psychiatric disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents is depolarized in KCC2 knockdown neurons, this shift is compensated by depolarization of the resting membrane potential. This reflects downregulation of leak potassium currents. We show KCC2 interacts with Task-3 (KCNK9) channels and is required for their membrane expression. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis, which could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that perturb network activity thus offering additional targets for therapeutic intervention. : Reduced KCC2 expression is associated with numerous neurological and psychiatric disorders and assumed to primarily affect GABA signaling. Goutierre et al. demonstrate chronic KCC2 knockdown in rat hippocampus has little effect on GABA signaling but affects neuronal excitability and network activity by downregulating membrane expression of Task-3 leak potassium channels. Keywords: KCC2, hippocampus, epilepsy, chloride, GABA, synaptic transmission, transporter, K2P, leak channels, dentate gyrushttp://www.sciencedirect.com/science/article/pii/S2211124719307594 |
| spellingShingle | Marie Goutierre Sana Al Awabdh Florian Donneger Emeline François Daniel Gomez-Dominguez Theano Irinopoulou Liset Menendez de la Prida Jean Christophe Poncer KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels Cell Reports |
| title | KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels |
| title_full | KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels |
| title_fullStr | KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels |
| title_full_unstemmed | KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels |
| title_short | KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels |
| title_sort | kcc2 regulates neuronal excitability and hippocampal activity via interaction with task 3 channels |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719307594 |
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