PMC:6891841 / 17498-20983 JSONTXT

{"project":"0_colil","denotations":[{"id":"31232111-1334669-2439","span":{"begin":459,"end":461},"obj":"1334669"},{"id":"31232111-1334666-2440","span":{"begin":462,"end":464},"obj":"1334666"},{"id":"31232111-22998871-2442","span":{"begin":845,"end":847},"obj":"22998871"},{"id":"31232111-27075542-2443","span":{"begin":1451,"end":1453},"obj":"27075542"},{"id":"31232111-27075542-2444","span":{"begin":1725,"end":1727},"obj":"27075542"},{"id":"31232111-23660230-2445","span":{"begin":2418,"end":2420},"obj":"23660230"},{"id":"31232111-9547246-2446","span":{"begin":2587,"end":2589},"obj":"9547246"},{"id":"31232111-9547246-2447","span":{"begin":2742,"end":2744},"obj":"9547246"},{"id":"31232111-6316152-2448","span":{"begin":2997,"end":2999},"obj":"6316152"},{"id":"31232111-25752305-2449","span":{"begin":3376,"end":3378},"obj":"25752305"}],"text":"Do Granule Cells Cause Seizures?\nAlthough work described above reflected substantial progress in understanding the DG in TLE, an essential assumption about the DG in TLE was untested: It had not been shown that the GCs could ever initiate a seizure in vivo. The first hypotheses along these lines developed in the early 1980s when it was suggested that the GC population was similar to a gate or filter, normally preventing seizures from entering CA3 and CA1.61,62 Many supportive studies of this “gate” hypothesis have been done over the decades, but no recordings have been made in vivo showing the GCs initiate a seizure. On the other hand, it appears to be possible for hypertrophied GCs to initiate seizures, making this type of GC (and the mammalian target of rapamycin pathway that controls their formation), assume new importance in TLE.63\nRecent studies suggest how GCs could cause a seizure. One hypothesis has emerged from 2 lines of research that have attracted a great deal of attention: (1) one research area defined the potential mechanisms underlying the transition to seizures, and (2) another research area clarified characteristics of GC transmission to area CA3 pyramidal cells. Regarding the transition to seizures, the arguments about a single transition have been supplanted by the view, based on observations in clinical recordings, that there are multiple types of seizures in TLE and therefore different types of transitions.64 Notably, one seizure type has been identified as primarily initiating in area CA3, and it may be no coincidence that these pyramidal cells have a very special type of synapse from GCs that can promote seizures. This type of seizure has been named hypersynchronous or HYP.64 It begins when principal cells begin to synchronize, and an important contribution is failure of inhibition in the local circuit that typically keeps the principal cells from synchronizing. In separate experiments, it has been shown that, despite the quiescence of GCs normally, when they begin to fire they can have dramatically excitatory effects on their target neurons in area CA3. One of the reasons is the axon of the GC which has a “massive” axon bouton. The boutons of the GCs are packed with glutamatergic vesicles and peptides like brain-derived neurotrophic factor (BDNF) that facilitate more glutamate release, leading to even more excitation of GC targets than glutamate alone.65 In fact, BDNF itself has been suggested to be critical in TLE.66 The massive boutons of GCs are largely on the pyramidal cells, with smaller ones on inhibitory cells.67 Therefore, based on this view, there is potential for GCs to strongly excite pyramidal cells more than inhibitory cells, although there are other views.67 It is noteworthy that pyramidal cells in CA3 form recurrent excitatory connections normally, and even the discharge of one pyramidal cell can lead to a population discharge, a finding that was highlighted many years ago because of its relevance to TLE.68 In summary, GCs can powerfully excite CA3 and have often been called potential “detonators.” Thus, the characteristics of GCs and CA3 (and perhaps EGCs) appear to be ideal to underlie a HYP seizure transition.\nResearch with selective new methods such as optogenetics are now addressing these ideas, although there is not always support for the idea that GCs initiate seizures.69 Therefore, there is still a lot to be done. This is an “exciting” time to be conducting epilepsy research."}

{"project":"TEST0","denotations":[{"id":"31232111-201-207-2439","span":{"begin":459,"end":461},"obj":"[\"1334669\"]"},{"id":"31232111-204-210-2440","span":{"begin":462,"end":464},"obj":"[\"1334666\"]"},{"id":"31232111-220-226-2442","span":{"begin":845,"end":847},"obj":"[\"22998871\"]"},{"id":"31232111-227-233-2443","span":{"begin":1451,"end":1453},"obj":"[\"27075542\"]"},{"id":"31232111-236-242-2444","span":{"begin":1725,"end":1727},"obj":"[\"27075542\"]"},{"id":"31232111-236-242-2445","span":{"begin":2418,"end":2420},"obj":"[\"23660230\"]"},{"id":"31232111-236-242-2446","span":{"begin":2587,"end":2589},"obj":"[\"9547246\"]"},{"id":"31232111-155-161-2447","span":{"begin":2742,"end":2744},"obj":"[\"9547246\"]"},{"id":"31232111-235-241-2448","span":{"begin":2997,"end":2999},"obj":"[\"6316152\"]"},{"id":"31232111-166-172-2449","span":{"begin":3376,"end":3378},"obj":"[\"25752305\"]"}],"text":"Do Granule Cells Cause Seizures?\nAlthough work described above reflected substantial progress in understanding the DG in TLE, an essential assumption about the DG in TLE was untested: It had not been shown that the GCs could ever initiate a seizure in vivo. The first hypotheses along these lines developed in the early 1980s when it was suggested that the GC population was similar to a gate or filter, normally preventing seizures from entering CA3 and CA1.61,62 Many supportive studies of this “gate” hypothesis have been done over the decades, but no recordings have been made in vivo showing the GCs initiate a seizure. On the other hand, it appears to be possible for hypertrophied GCs to initiate seizures, making this type of GC (and the mammalian target of rapamycin pathway that controls their formation), assume new importance in TLE.63\nRecent studies suggest how GCs could cause a seizure. One hypothesis has emerged from 2 lines of research that have attracted a great deal of attention: (1) one research area defined the potential mechanisms underlying the transition to seizures, and (2) another research area clarified characteristics of GC transmission to area CA3 pyramidal cells. Regarding the transition to seizures, the arguments about a single transition have been supplanted by the view, based on observations in clinical recordings, that there are multiple types of seizures in TLE and therefore different types of transitions.64 Notably, one seizure type has been identified as primarily initiating in area CA3, and it may be no coincidence that these pyramidal cells have a very special type of synapse from GCs that can promote seizures. This type of seizure has been named hypersynchronous or HYP.64 It begins when principal cells begin to synchronize, and an important contribution is failure of inhibition in the local circuit that typically keeps the principal cells from synchronizing. In separate experiments, it has been shown that, despite the quiescence of GCs normally, when they begin to fire they can have dramatically excitatory effects on their target neurons in area CA3. One of the reasons is the axon of the GC which has a “massive” axon bouton. The boutons of the GCs are packed with glutamatergic vesicles and peptides like brain-derived neurotrophic factor (BDNF) that facilitate more glutamate release, leading to even more excitation of GC targets than glutamate alone.65 In fact, BDNF itself has been suggested to be critical in TLE.66 The massive boutons of GCs are largely on the pyramidal cells, with smaller ones on inhibitory cells.67 Therefore, based on this view, there is potential for GCs to strongly excite pyramidal cells more than inhibitory cells, although there are other views.67 It is noteworthy that pyramidal cells in CA3 form recurrent excitatory connections normally, and even the discharge of one pyramidal cell can lead to a population discharge, a finding that was highlighted many years ago because of its relevance to TLE.68 In summary, GCs can powerfully excite CA3 and have often been called potential “detonators.” Thus, the characteristics of GCs and CA3 (and perhaps EGCs) appear to be ideal to underlie a HYP seizure transition.\nResearch with selective new methods such as optogenetics are now addressing these ideas, although there is not always support for the idea that GCs initiate seizures.69 Therefore, there is still a lot to be done. This is an “exciting” time to be conducting epilepsy research."}

{"project":"2_test","denotations":[{"id":"31232111-1334669-28640037","span":{"begin":459,"end":461},"obj":"1334669"},{"id":"31232111-1334666-28640038","span":{"begin":462,"end":464},"obj":"1334666"},{"id":"31232111-22998871-28640040","span":{"begin":845,"end":847},"obj":"22998871"},{"id":"31232111-27075542-28640041","span":{"begin":1451,"end":1453},"obj":"27075542"},{"id":"31232111-27075542-28640042","span":{"begin":1725,"end":1727},"obj":"27075542"},{"id":"31232111-23660230-28640043","span":{"begin":2418,"end":2420},"obj":"23660230"},{"id":"31232111-9547246-28640044","span":{"begin":2587,"end":2589},"obj":"9547246"},{"id":"31232111-9547246-28640045","span":{"begin":2742,"end":2744},"obj":"9547246"},{"id":"31232111-6316152-28640046","span":{"begin":2997,"end":2999},"obj":"6316152"},{"id":"31232111-25752305-28640047","span":{"begin":3376,"end":3378},"obj":"25752305"}],"text":"Do Granule Cells Cause Seizures?\nAlthough work described above reflected substantial progress in understanding the DG in TLE, an essential assumption about the DG in TLE was untested: It had not been shown that the GCs could ever initiate a seizure in vivo. The first hypotheses along these lines developed in the early 1980s when it was suggested that the GC population was similar to a gate or filter, normally preventing seizures from entering CA3 and CA1.61,62 Many supportive studies of this “gate” hypothesis have been done over the decades, but no recordings have been made in vivo showing the GCs initiate a seizure. On the other hand, it appears to be possible for hypertrophied GCs to initiate seizures, making this type of GC (and the mammalian target of rapamycin pathway that controls their formation), assume new importance in TLE.63\nRecent studies suggest how GCs could cause a seizure. One hypothesis has emerged from 2 lines of research that have attracted a great deal of attention: (1) one research area defined the potential mechanisms underlying the transition to seizures, and (2) another research area clarified characteristics of GC transmission to area CA3 pyramidal cells. Regarding the transition to seizures, the arguments about a single transition have been supplanted by the view, based on observations in clinical recordings, that there are multiple types of seizures in TLE and therefore different types of transitions.64 Notably, one seizure type has been identified as primarily initiating in area CA3, and it may be no coincidence that these pyramidal cells have a very special type of synapse from GCs that can promote seizures. This type of seizure has been named hypersynchronous or HYP.64 It begins when principal cells begin to synchronize, and an important contribution is failure of inhibition in the local circuit that typically keeps the principal cells from synchronizing. In separate experiments, it has been shown that, despite the quiescence of GCs normally, when they begin to fire they can have dramatically excitatory effects on their target neurons in area CA3. One of the reasons is the axon of the GC which has a “massive” axon bouton. The boutons of the GCs are packed with glutamatergic vesicles and peptides like brain-derived neurotrophic factor (BDNF) that facilitate more glutamate release, leading to even more excitation of GC targets than glutamate alone.65 In fact, BDNF itself has been suggested to be critical in TLE.66 The massive boutons of GCs are largely on the pyramidal cells, with smaller ones on inhibitory cells.67 Therefore, based on this view, there is potential for GCs to strongly excite pyramidal cells more than inhibitory cells, although there are other views.67 It is noteworthy that pyramidal cells in CA3 form recurrent excitatory connections normally, and even the discharge of one pyramidal cell can lead to a population discharge, a finding that was highlighted many years ago because of its relevance to TLE.68 In summary, GCs can powerfully excite CA3 and have often been called potential “detonators.” Thus, the characteristics of GCs and CA3 (and perhaps EGCs) appear to be ideal to underlie a HYP seizure transition.\nResearch with selective new methods such as optogenetics are now addressing these ideas, although there is not always support for the idea that GCs initiate seizures.69 Therefore, there is still a lot to be done. This is an “exciting” time to be conducting epilepsy research."}

{"project":"MyTest","denotations":[{"id":"31232111-1334669-28640037","span":{"begin":459,"end":461},"obj":"1334669"},{"id":"31232111-1334666-28640038","span":{"begin":462,"end":465},"obj":"1334666"},{"id":"31232111-22998871-28640040","span":{"begin":845,"end":848},"obj":"22998871"},{"id":"31232111-27075542-28640041","span":{"begin":1451,"end":1454},"obj":"27075542"},{"id":"31232111-27075542-28640042","span":{"begin":1725,"end":1728},"obj":"27075542"},{"id":"31232111-23660230-28640043","span":{"begin":2418,"end":2421},"obj":"23660230"},{"id":"31232111-9547246-28640044","span":{"begin":2587,"end":2590},"obj":"9547246"},{"id":"31232111-9547246-28640045","span":{"begin":2742,"end":2745},"obj":"9547246"},{"id":"31232111-6316152-28640046","span":{"begin":2997,"end":3000},"obj":"6316152"},{"id":"31232111-25752305-28640047","span":{"begin":3376,"end":3379},"obj":"25752305"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Do Granule Cells Cause Seizures?\nAlthough work described above reflected substantial progress in understanding the DG in TLE, an essential assumption about the DG in TLE was untested: It had not been shown that the GCs could ever initiate a seizure in vivo. The first hypotheses along these lines developed in the early 1980s when it was suggested that the GC population was similar to a gate or filter, normally preventing seizures from entering CA3 and CA1.61,62 Many supportive studies of this “gate” hypothesis have been done over the decades, but no recordings have been made in vivo showing the GCs initiate a seizure. On the other hand, it appears to be possible for hypertrophied GCs to initiate seizures, making this type of GC (and the mammalian target of rapamycin pathway that controls their formation), assume new importance in TLE.63\nRecent studies suggest how GCs could cause a seizure. One hypothesis has emerged from 2 lines of research that have attracted a great deal of attention: (1) one research area defined the potential mechanisms underlying the transition to seizures, and (2) another research area clarified characteristics of GC transmission to area CA3 pyramidal cells. Regarding the transition to seizures, the arguments about a single transition have been supplanted by the view, based on observations in clinical recordings, that there are multiple types of seizures in TLE and therefore different types of transitions.64 Notably, one seizure type has been identified as primarily initiating in area CA3, and it may be no coincidence that these pyramidal cells have a very special type of synapse from GCs that can promote seizures. This type of seizure has been named hypersynchronous or HYP.64 It begins when principal cells begin to synchronize, and an important contribution is failure of inhibition in the local circuit that typically keeps the principal cells from synchronizing. In separate experiments, it has been shown that, despite the quiescence of GCs normally, when they begin to fire they can have dramatically excitatory effects on their target neurons in area CA3. One of the reasons is the axon of the GC which has a “massive” axon bouton. The boutons of the GCs are packed with glutamatergic vesicles and peptides like brain-derived neurotrophic factor (BDNF) that facilitate more glutamate release, leading to even more excitation of GC targets than glutamate alone.65 In fact, BDNF itself has been suggested to be critical in TLE.66 The massive boutons of GCs are largely on the pyramidal cells, with smaller ones on inhibitory cells.67 Therefore, based on this view, there is potential for GCs to strongly excite pyramidal cells more than inhibitory cells, although there are other views.67 It is noteworthy that pyramidal cells in CA3 form recurrent excitatory connections normally, and even the discharge of one pyramidal cell can lead to a population discharge, a finding that was highlighted many years ago because of its relevance to TLE.68 In summary, GCs can powerfully excite CA3 and have often been called potential “detonators.” Thus, the characteristics of GCs and CA3 (and perhaps EGCs) appear to be ideal to underlie a HYP seizure transition.\nResearch with selective new methods such as optogenetics are now addressing these ideas, although there is not always support for the idea that GCs initiate seizures.69 Therefore, there is still a lot to be done. This is an “exciting” time to be conducting epilepsy research."}

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The first hypotheses along these lines developed in the early 1980s when it was suggested that the GC population was similar to a gate or filter, normally preventing seizures from entering CA3 and CA1.61,62 Many supportive studies of this “gate” hypothesis have been done over the decades, but no recordings have been made in vivo showing the GCs initiate a seizure. On the other hand, it appears to be possible for hypertrophied GCs to initiate seizures, making this type of GC (and the mammalian target of rapamycin pathway that controls their formation), assume new importance in TLE.63\nRecent studies suggest how GCs could cause a seizure. One hypothesis has emerged from 2 lines of research that have attracted a great deal of attention: (1) one research area defined the potential mechanisms underlying the transition to seizures, and (2) another research area clarified characteristics of GC transmission to area CA3 pyramidal cells. Regarding the transition to seizures, the arguments about a single transition have been supplanted by the view, based on observations in clinical recordings, that there are multiple types of seizures in TLE and therefore different types of transitions.64 Notably, one seizure type has been identified as primarily initiating in area CA3, and it may be no coincidence that these pyramidal cells have a very special type of synapse from GCs that can promote seizures. This type of seizure has been named hypersynchronous or HYP.64 It begins when principal cells begin to synchronize, and an important contribution is failure of inhibition in the local circuit that typically keeps the principal cells from synchronizing. In separate experiments, it has been shown that, despite the quiescence of GCs normally, when they begin to fire they can have dramatically excitatory effects on their target neurons in area CA3. One of the reasons is the axon of the GC which has a “massive” axon bouton. The boutons of the GCs are packed with glutamatergic vesicles and peptides like brain-derived neurotrophic factor (BDNF) that facilitate more glutamate release, leading to even more excitation of GC targets than glutamate alone.65 In fact, BDNF itself has been suggested to be critical in TLE.66 The massive boutons of GCs are largely on the pyramidal cells, with smaller ones on inhibitory cells.67 Therefore, based on this view, there is potential for GCs to strongly excite pyramidal cells more than inhibitory cells, although there are other views.67 It is noteworthy that pyramidal cells in CA3 form recurrent excitatory connections normally, and even the discharge of one pyramidal cell can lead to a population discharge, a finding that was highlighted many years ago because of its relevance to TLE.68 In summary, GCs can powerfully excite CA3 and have often been called potential “detonators.” Thus, the characteristics of GCs and CA3 (and perhaps EGCs) appear to be ideal to underlie a HYP seizure transition.\nResearch with selective new methods such as optogenetics are now addressing these ideas, although there is not always support for the idea that GCs initiate seizures.69 Therefore, there is still a lot to be done. This is an “exciting” time to be conducting epilepsy research."}