Ontogeny and topography of seizure regulation by the substantia nigra

Moshé, Solomon L.; Garant, Douglas S.; Sperber, Ellen F.; VELIKOVA, J; Kubová, Hana; Brown, Lisa

doi:10.1016/0387-7604(95)90074-8

Cited by 11 publications

(6 citation statements)

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“…Impaired awareness is particularly prevalent when the age of diabetes diagnosis is early (<6 years) and is associated with recurrent hypoglycemic episodes resulting in seizures or coma [48] though other studies have reported conflicting results [18] , [20] . In addition, animal studies have demonstrated the increased susceptibility of the juvenile brain to neuronal excitability and seizures [34] , [36] , [49] and shorter latency to seizure generalization [45] . While there are several clinical studies that have assessed the effects of seizures such as EEG abnormalities [37] and increased cognitive impairmanet [50] , the specific incidence of hypoglycemic seizures is unknown.…”

Section: Discussionmentioning

confidence: 99%

Severe Hypoglycemia in a Juvenile Diabetic Rat Model: Presence and Severity of Seizures Are Associated with Mortality

Mylvaganam

El-Hayek

et al. 2013

PLoS ONE

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It is well accepted that insulin-induced hypoglycemia can result in seizures. However, the effects of the seizures, as well as possible treatment strategies, have yet to be elucidated, particularly in juvenile or insulin-dependent diabetes mellitus (IDDM). Here we establish a model of diabetes in young rats, to examine the consequences of severe hypoglycemia in this age group; particularly seizures and mortality. Diabetes was induced in post-weaned 22-day-old Sprague-Dawley rats by streptozotocin (STZ) administered intraperitoneally (IP). Insulin IP (15 U/kg), in rats fasted (14–16 hours), induced hypoglycemia, defined as <3.5 mM blood glucose (BG), in 68% of diabetic (STZ) and 86% of control rats (CON). Seizures occurred in 86% of STZ and all CON rats that reached hypoglycemic levels with mortality only occurring post-seizure. The fasting BG levels were significantly higher in STZ (12.4±1.3 mM) than in CON rodents (6.3±0.3 mM), resulting in earlier onset of hypoglycemia and seizures in the CON group. However, the BG at seizure onset was statistically similar between STZ (1.8±0.2 mM) and CON animals (1.6±0.1 mM) as well as between those that survived (S+S) and those that died (S+M) post-seizure. Despite this, the S+M group underwent a significantly greater number of seizure events than the S+S group. 25% glucose administered at seizure onset and repeated with recurrent seizures was not sufficient to mitigate these continued convulsions. Combining glucose with diazepam and phenytoin significantly decreased post-treatment seizures, but not mortality. Intracranial electroencephalograms (EEGs) were recorded in 10 CON and 9 STZ animals. Predictive EEG changes were not observed in these animals that underwent seizures. Fluorojade staining revealed damaged cells in non-seizing STZ animals and in STZ and CON animals post-seizure. In summary, this model of hypoglycemia and seizures in juvenile diabetic rats provides a paradigm for further study of underlying mechanisms. Our data demonstrate that severe hypoglycemia (<2.0 mM) is a necessary precondition for seizures, and the increased frequency of these seizures is associated with mortality.

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Section: Discussionmentioning

confidence: 99%

Severe Hypoglycemia in a Juvenile Diabetic Rat Model: Presence and Severity of Seizures Are Associated with Mortality

Mylvaganam

El-Hayek

et al. 2013

PLoS ONE

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“…While there have been several reports regarding the topography of nigral-mediated anticonvulsant effects in rodents, we targeted a region that has proved consistently effective across studies (i.e., the anterior SNpr, at a level in which the region sometimes described as the "pars lateralis" is present) (18,65). Moreover, this region robustly projects to the deep and intermediate layers of the SC (18).…”

Section: Discussionmentioning

confidence: 99%

Descending projections from the substantia nigra pars reticulata differentially control seizures

Wicker

Beck

Kulick-Soper

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Three decades of studies have shown that inhibition of thesubstantia nigra pars reticulata(SNpr) attenuates seizures, yet the circuits mediating this effect remain obscure. SNpr projects to the deep and intermediate layers of the superior colliculus (DLSC) and the pedunculopontine nucleus (PPN), but the contributions of these projections are unknown. To address this gap, we optogenetically silenced cell bodies within SNpr, nigrotectal terminals within DLSC, and nigrotegmental terminals within PPN. Inhibition of cell bodies in SNpr suppressed generalized seizures evoked by pentylenetetrazole (PTZ), partial seizures evoked from the forebrain, absence seizures evoked by gamma-butyrolactone (GBL), and audiogenic seizures in genetically epilepsy-prone rats. Strikingly, these effects were fully recapitulated by silencing nigrotectal projections. By contrast, silencing nigrotegmental terminals reduced only absence seizures and exacerbated seizures evoked by PTZ. These data underscore the broad-spectrum anticonvulsant efficacy of this circuit, and demonstrate that specific efferent projection pathways differentially control different seizure types.

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“…For epilepsy patients with multiple foci or without a clear focal onset, therapeutic manipulation of key structures within seizure-suppressing circuits may be a promising strategy. Studies on different seizure or epilepsy models imply that especially the SNr may be of particular interest in this respect, because bilateral microinjection of drugs that either increase GABAergic inhibition or reduce glutamatergic excitation in the SNr prevents or attenuates different experimentally induced seizure types (20, 24,33,35,37,46,48,55,59,82). Accordingly, using [ 3 H]2-deoxyglucose mapping, the SNr has been shown to be activated during different experimentally induced generalized seizures including PTZ-induced convulsions (4).…”

Section: Discussionmentioning

confidence: 99%

“…This is especially true for the substantia nigra pars reticulata (SNr), a basal ganglia output structure that has been shown to be a common final path for the propagation and modulation of seizure activity (20,35,46). There is ample evidence that inhibition of the SNr by bilateral microinjection of drugs, which increase GABAergic or decrease glutamatergic function, or by bilateral grafting of GABA-producing cells suppresses or reduces a large number of different seizure types (15,20,22,24,35,46,48,52,55,59,63,82,86).…”

Section: Introductionmentioning

confidence: 99%

Anticonvulsant Effects by Bilateral and Unilateral Transplantation of GABA-Producing Cells into the Subthalamic Nucleus in an Acute Seizure Model

et al. 2014

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Neural transplantation of GABA-producing cells into key structures within seizure-suppressing circuits holds promise for medication-resistant epilepsy patients not eligible for resection of the epileptic focus. The substantia nigra pars reticulata (SNr), a basal ganglia output structure, is well known to modulate different seizure types. A recent microinjection study by our group indicated that the subthalamic nucleus (STN), which critically regulates nigral activity, might be a more promising target for focal therapy in epilepsies than the SNr. As a proof of principle, we therefore assessed the anticonvulsant efficacy of bilateral and unilateral allografting of GABA-producing cell lines into the STN using the timed intravenous pentylenetetrazole seizure threshold test, which allows repeated seizure threshold determinations in individual rats. We observed (a) that grafted cells survived up to the end of the experiments, (b) that anticonvulsant effects can be induced by bilateral transplantation into the STN using immortalized GABAergic cells derived from the rat embryonic striatum and cells additionally transfected to obtain higher GABA synthesis than the parent cell line, and (c) that anticonvulsant effects were observed even after unilateral transplantation into the STN. Neither grafting of control cells nor transplantation outside the STN induced anticonvulsant effects, emphasizing the site and cell specificity of the observed anticonvulsant effects. To our knowledge, the present study is the first showing anticonvulsant effects by grafting of GABA-producing cells into the STN. The STN can be considered a highly promising target region for modulation of seizure circuits and, moreover, has the advantage of being clinically established for functional neurosurgery.

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Ontogeny and topography of seizure regulation by the substantia nigra

Cited by 11 publications

References 0 publications

Severe Hypoglycemia in a Juvenile Diabetic Rat Model: Presence and Severity of Seizures Are Associated with Mortality

Severe Hypoglycemia in a Juvenile Diabetic Rat Model: Presence and Severity of Seizures Are Associated with Mortality

Descending projections from the substantia nigra pars reticulata differentially control seizures

Anticonvulsant Effects by Bilateral and Unilateral Transplantation of GABA-Producing Cells into the Subthalamic Nucleus in an Acute Seizure Model

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