Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy
Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ i...
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Elsevier
2024-12-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003395 |
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| author | Sang-Hun Lee Young-Jin Kang Bret N. Smith |
| author_facet | Sang-Hun Lee Young-Jin Kang Bret N. Smith |
| author_sort | Sang-Hun Lee |
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| description | Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ interneuron mediated inhibition is compromised in the dentate gyrus shortly after status epilepticus, contributing to epileptogenesis in temporal lobe epilepsy. It is uncertain whether the impaired activity of dentate PV+ interneurons recovers at later times or if it continues for months following status epilepticus. The development of compensatory modifications related to PV+ interneuron circuits in the months following status epilepticus is unknown, although reduced dentate GABAergic inhibition persists long after status epilepticus. We employed whole-cell patch-clamp recordings from dentate PV+ interneurons and DGCs in slices from male and female sham controls and intrahippocampal kainate (IHK) treated mice that developed spontaneous seizures months after status epilepticus to study epilepsy-associated changes in dentate PV+ interneuron circuits. Electrical recordings showed that: 1) Action potential firing rates of dentate PV+ interneurons were reduced in IHK treated mice up to four months after status epilepticus; 2) spontaneous inhibitory postsynaptic currents (sIPSCs) in DGCs exhibited reduced frequency but increased amplitude in IHK treated mice; and 3) the amplitude of IPSCs in DGCs evoked by optogenetic activation of dentate PV+ cells was upregulated without changes in short-term plasticity. Video-EEG recordings revealed that IHK treated mice showed spontaneous electrographic seizures in the dentate gyrus and that chemogenetic activation of PV+ interneurons abolished electrographic seizures. Our results suggest not only that the compensatory changes in PV+ interneuron circuits develop after IHK treatment, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for cell loss and reduced intrinsic excitability of dentate PV+ interneurons to stop seizures in temporal lobe epilepsy. |
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| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj-art-bcd3309bbe7d4b9eb6d86e8797b69ef92025-08-20T02:37:45ZengElsevierNeurobiology of Disease1095-953X2024-12-0120310673710.1016/j.nbd.2024.106737Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsySang-Hun Lee0Young-Jin Kang1Bret N. Smith2Corresponding authors at: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.; Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USADepartment of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USACorresponding authors at: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.; Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USAParvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ interneuron mediated inhibition is compromised in the dentate gyrus shortly after status epilepticus, contributing to epileptogenesis in temporal lobe epilepsy. It is uncertain whether the impaired activity of dentate PV+ interneurons recovers at later times or if it continues for months following status epilepticus. The development of compensatory modifications related to PV+ interneuron circuits in the months following status epilepticus is unknown, although reduced dentate GABAergic inhibition persists long after status epilepticus. We employed whole-cell patch-clamp recordings from dentate PV+ interneurons and DGCs in slices from male and female sham controls and intrahippocampal kainate (IHK) treated mice that developed spontaneous seizures months after status epilepticus to study epilepsy-associated changes in dentate PV+ interneuron circuits. Electrical recordings showed that: 1) Action potential firing rates of dentate PV+ interneurons were reduced in IHK treated mice up to four months after status epilepticus; 2) spontaneous inhibitory postsynaptic currents (sIPSCs) in DGCs exhibited reduced frequency but increased amplitude in IHK treated mice; and 3) the amplitude of IPSCs in DGCs evoked by optogenetic activation of dentate PV+ cells was upregulated without changes in short-term plasticity. Video-EEG recordings revealed that IHK treated mice showed spontaneous electrographic seizures in the dentate gyrus and that chemogenetic activation of PV+ interneurons abolished electrographic seizures. Our results suggest not only that the compensatory changes in PV+ interneuron circuits develop after IHK treatment, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for cell loss and reduced intrinsic excitability of dentate PV+ interneurons to stop seizures in temporal lobe epilepsy.http://www.sciencedirect.com/science/article/pii/S0969996124003395Temporal lobe epilepsyGABAergic interneuronParvalbumin-expressing basket cellDentate gyrus |
| spellingShingle | Sang-Hun Lee Young-Jin Kang Bret N. Smith Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy Neurobiology of Disease Temporal lobe epilepsy GABAergic interneuron Parvalbumin-expressing basket cell Dentate gyrus |
| title | Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy |
| title_full | Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy |
| title_fullStr | Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy |
| title_full_unstemmed | Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy |
| title_short | Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy |
| title_sort | activation of hypoactive parvalbumin positive fast spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy |
| topic | Temporal lobe epilepsy GABAergic interneuron Parvalbumin-expressing basket cell Dentate gyrus |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003395 |
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