Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons
Studies in rodent epilepsy models suggest that GABAergic interneuron progenitor grafts can reduce hyperexcitability and seizures in temporal lobe epilepsy (TLE). Although integration of the transplanted cells has been proposed as the underlying mechanism for these disease-modifying effects, prior st...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Society for Neuroscience
2015
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| Online Access: | http://hdl.handle.net/1721.1/96902 |
| _version_ | 1811096128714702848 |
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| author | Henderson, K. W. Gupta, J. Litvina, E. Zheng, X. Van Zandt, M. A. Woods, N. Grund, E. Lin, D. Royston, S. Yanagawa, Y. Aaron, G. B. Naegele, J. R. Tagliatela, Stephanie |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Henderson, K. W. Gupta, J. Litvina, E. Zheng, X. Van Zandt, M. A. Woods, N. Grund, E. Lin, D. Royston, S. Yanagawa, Y. Aaron, G. B. Naegele, J. R. Tagliatela, Stephanie |
| author_sort | Henderson, K. W. |
| collection | MIT |
| description | Studies in rodent epilepsy models suggest that GABAergic interneuron progenitor grafts can reduce hyperexcitability and seizures in temporal lobe epilepsy (TLE). Although integration of the transplanted cells has been proposed as the underlying mechanism for these disease-modifying effects, prior studies have not explicitly examined cell types and synaptic mechanisms for long-term seizure suppression. To address this gap, we transplanted medial ganglionic eminence (MGE) cells from embryonic day 13.5 VGAT-Venus or VGAT-ChR2-EYFP transgenic embryos into the dentate gyrus (DG) of adult mice 2 weeks after induction of TLE with pilocarpine. Beginning 3–4 weeks after status epilepticus, we conducted continuous video-electroencephalographic recording until 90–100 d. TLE mice with bilateral MGE cell grafts in the DG had significantly fewer and milder electrographic seizures, compared with TLE controls. Immunohistochemical studies showed that the transplants contained multiple neuropeptide or calcium-binding protein-expressing interneuron types and these cells established dense terminal arborizations onto the somas, apical dendrites, and axon initial segments of dentate granule cells (GCs). A majority of the synaptic terminals formed by the transplanted cells were apposed to large postsynaptic clusters of gephyrin, indicative of mature inhibitory synaptic complexes. Functionality of these new inhibitory synapses was demonstrated by optogenetically activating VGAT-ChR2-EYFP-expressing transplanted neurons, which generated robust hyperpolarizations in GCs. These findings suggest that fetal GABAergic interneuron grafts may suppress pharmacoresistant seizures by enhancing synaptic inhibition in DG neural circuits. |
| first_indexed | 2024-09-23T16:38:37Z |
| format | Article |
| id | mit-1721.1/96902 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:38:37Z |
| publishDate | 2015 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/969022022-09-29T20:30:23Z Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons Henderson, K. W. Gupta, J. Litvina, E. Zheng, X. Van Zandt, M. A. Woods, N. Grund, E. Lin, D. Royston, S. Yanagawa, Y. Aaron, G. B. Naegele, J. R. Tagliatela, Stephanie Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Tagliatela, Stephanie Studies in rodent epilepsy models suggest that GABAergic interneuron progenitor grafts can reduce hyperexcitability and seizures in temporal lobe epilepsy (TLE). Although integration of the transplanted cells has been proposed as the underlying mechanism for these disease-modifying effects, prior studies have not explicitly examined cell types and synaptic mechanisms for long-term seizure suppression. To address this gap, we transplanted medial ganglionic eminence (MGE) cells from embryonic day 13.5 VGAT-Venus or VGAT-ChR2-EYFP transgenic embryos into the dentate gyrus (DG) of adult mice 2 weeks after induction of TLE with pilocarpine. Beginning 3–4 weeks after status epilepticus, we conducted continuous video-electroencephalographic recording until 90–100 d. TLE mice with bilateral MGE cell grafts in the DG had significantly fewer and milder electrographic seizures, compared with TLE controls. Immunohistochemical studies showed that the transplants contained multiple neuropeptide or calcium-binding protein-expressing interneuron types and these cells established dense terminal arborizations onto the somas, apical dendrites, and axon initial segments of dentate granule cells (GCs). A majority of the synaptic terminals formed by the transplanted cells were apposed to large postsynaptic clusters of gephyrin, indicative of mature inhibitory synaptic complexes. Functionality of these new inhibitory synapses was demonstrated by optogenetically activating VGAT-ChR2-EYFP-expressing transplanted neurons, which generated robust hyperpolarizations in GCs. These findings suggest that fetal GABAergic interneuron grafts may suppress pharmacoresistant seizures by enhancing synaptic inhibition in DG neural circuits. 2015-05-04T16:27:34Z 2015-05-04T16:27:34Z 2014-10 2014-07 Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/96902 Henderson, K. W., J. Gupta, S. Tagliatela, E. Litvina, X. Zheng, M. A. Van Zandt, N. Woods, et al. “Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons.” Journal of Neuroscience 34, no. 40 (October 1, 2014): 13492–13504. en_US http://dx.doi.org/10.1523/jneurosci.0005-14.2014 Journal of Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Society for Neuroscience Society for Neuroscience |
| spellingShingle | Henderson, K. W. Gupta, J. Litvina, E. Zheng, X. Van Zandt, M. A. Woods, N. Grund, E. Lin, D. Royston, S. Yanagawa, Y. Aaron, G. B. Naegele, J. R. Tagliatela, Stephanie Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons |
| title | Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons |
| title_full | Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons |
| title_fullStr | Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons |
| title_full_unstemmed | Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons |
| title_short | Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons |
| title_sort | long term seizure suppression and optogenetic analyses of synaptic connectivity in epileptic mice with hippocampal grafts of gabaergic interneurons |
| url | http://hdl.handle.net/1721.1/96902 |
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