A selective loss of somatostatin in the hippocampus of patients with temporal lobe epilepsy

Robbins, Richard J.; Brines, Michael; Kim, Jung Ho; Adrian, Thomas E.; Lanerolle, Nihal de; Welsh, Susan; Spencer, Dennis D.

doi:10.1002/ana.410290316

Cited by 203 publications

(95 citation statements)

References 51 publications

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“…Double labeling for somatostatin revealed that STEP was enriched in somatostatinergic hilar interneurons. As noted above, this subclass of interneurons is highly vulnerable to SE-induced excitotoxicity (Robbins et al, 1991;Buckmaster and Jongen-Rélo, 1999). We found that acute SE-induced cell death was correlated with STEP expression in the hilus.…”

Section: Discussionsupporting

confidence: 78%

“…Of note is the marked decrease in somatostatin-positive interneurons both in patients with TLE (de Lanerolle et al, 1989;Robbins et al, 1991) and in animal models of TLE (Sloviter, 1987;Sloviter, 1991;Buckmaster and Dudek, 1997;Buckmaster and Jongen-Rélo, 1999). For example, postmortem analysis has revealed that the number of somatostatin-positive neurons is reduced by 80% in individuals with TLE (Robbins et al, 1991), and, in the kainic acid model of TLE, somatostatin-positive hilar interneurons account for Ͼ80% of the GABAergic cells that were lost (Buckmaster and JongenRélo, 1999). Given these observations, insight into the molecular mechanism responsible for the subclass-specific vulnerability of interneurons to SE-induced cell death may provide a deeper understanding of temporal lobe epileptogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

Choi¹,

Lin²,

Lee³

et al. 2007

J. Neurosci.

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Excitotoxic cell death is one of the precipitating events in the development of temporal lobe epilepsy. Of particular prominence is the loss of GABAergic hilar neurons. Although the molecular mechanisms responsible for the selective vulnerability of these cells are not well understood, activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway has been implicated in neuroprotective responses to excitotoxicity in other neuronal populations. Here, we report that high levels of the striatalenriched protein tyrosine phosphatase (STEP), a key regulator of ERK/MAPK signaling, are found in vulnerable somatostatinimmunoreactive hilar interneurons. Under both control conditions and after pilocarpine-induced status epilepticus (SE), ERK/MAPK activation was repressed in STEP-immunoreactive hilar neurons. This contrasts with robust SE-induced ERK/MAPK activation in the granule cell layer of the dentate gyrus, a cell region that does not express STEP. During pilocarpine-induced SE, in vivo disruption of STEP activity allowed activation of the MAPK pathway, leading to immediate-early gene expression and significant rescue from cell death. Thus, STEP increases the sensitivity of neurons to SE-induced excitotoxicity by specifically blocking a latent neuroprotective response initiated by the MAPK pathway. These findings identify a key set of signaling events that render somatostatinergic hilar interneurons vulnerable to SE-induced cell death.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

Choi¹,

Lin²,

Lee³

et al. 2007

J. Neurosci.

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“…Shortly thereafter, this specific pattern of neuron loss was confirmed in humans with temporal lobe epilepsy (de Lanerolle et al, 1989), and an upregulation of SST binding sites in human tissue was also noted (Robbins et al, 1991). Since these first reports, the loss of SST-containing hilar interneurons has been observed in many animal models, including kainate Sperk et al, 1992) and pilocarpine (Choi et al, 2007;Kobayashi and Buckmaster, 2003), and is now considered a hallmark of epileptic hippocampus.…”

Section: Seizures Induce the Loss Of Sst-containing Interneurons In Tmentioning

confidence: 87%

Somatostatin: An endogenous antiepileptic

Tallent

Qiu

2008

Molecular and Cellular Endocrinology

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The neuropeptide somatostatin is highly expressed in brain regions associated with seizures. In hippocampus, SST expression and release is regulated by seizures, and SST-containing neurons within the hilus of the dentate gyrus are sensitive to seizure-induced death. In vivo and in vitro studies suggest that the loss of SST function in the dentate could contribute to epileptogenesis and seizure susceptibility. SST also has inhibitory actions in the CA1 and CA3 hippocampus, indicating this peptide is an important homeostatic regulator throughout the hippocampus. In vivo studies show SST has robust antiepileptic properties, with the major site of action being hippocampus. In rodents, somatostatin receptor subtype 2 (SST 2 ) and SST 4 appear to mediate the majority of the antiepileptic actions of SST, with SST 2 predominate in rat and SST 4 in mouse. Thus SST receptors may be appropriate targets for new antiepileptic drugs, although validation in human tissue is lacking.

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“…So far, the anatomical and physiological basis for disinhibition of hippocampal pathways is not fully understood. Loss of other interneuronal subpopulations, such as somatostatin-and neuropeptide Y-containing interneurons (34)(35)(36), as well as of parvalbumin-immunoreactive inhibitory basket cells (37) in the hilus of human epilepsy specimens, could also play a role.…”

Section: Fig 3 Hilar Mossy Cells In the Human Hippocampusmentioning

confidence: 99%

Loss of Hilar Mossy Cells in Ammon's Horn Sclerosis

et al. 2000

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Summary:Purpose: Hilar mossy cells represent an important excitatory subpopulation of the hippocampal formation. Several studies have identified this cell type as particularly vulnerable to seizure activity in rat models of limbic epilepsy. Here we have subjected hilar mossy cell loss in the hippocampus of patients with chronic temporal lobe epilepsy (TLE) to a systematic morphological and immunohistochemical analysis.Methods: Hippocampal specimens from 30 TLE patients were included; 21 patients presented with segmental neuronal cell loss [Ammon's horns clerosis (AHS)] and 8 with focal lesions (tumors, scars, malformations) not involving the hippocampus proper. In one additional TLE patient, no histopathological alteration could be observed. Surgical specimens from tumor patients without epilepsy (n = 2) and nonepileptic autopsy brains (n = 8) were used as controls. Hilar mossy cells in the human hippocampus were visualized using a novel polycloncal antiserum directed against the metabotropic glutamate receptor subtype mGluR7b or by intracellular Lucifer Yellow injection, confocal laser scanning microscopy, and threedimensional morphological reconstruction.Results: Compared with controls, a significant loss of mGluR7 immunoreactive mossy cells was observed in patients with AHS (p < 0.05). In contrast, TLE patients with focal lesions but structurally intact hippocampus demonstrated only a discrete, nonsignificant reduction of this neuronal subpopulation. This observation was confirmed by analysis of 62 randomly injected hilar neurons from AHS patients, in which we were unable to detect neurons with a morphology like that of hilar mossy cells.Conclusion: Our present data indicate significant hilar mossy cell loss in TLE patients with AHS. In contrast, hilar mossy cells appear to be less vulnerable in patients with lesionassociated TLE. Although the significance of mGluR7 immunoreactivity in mossy cells remains to be studied, loss of this cell population is compatible with alterations in hippocampal networks and regional hyperexcitability as pathogenic mechanism of AHS and TLE. Key Words: Hippocampus-mGluRConfocal laser scanning microscopy-Epilepsy-Ammon's horn sclerosis-Seizures-Temporal lobe epilepsy.Approximately 60% of patients with mesial temporal lobe epilepsy show severe unilateral atrophy of the hippocampal formation (1). Histopathologically, the hippocampus of these patients reveals a stereotypical pattern of damage, with segmental neuronal cell loss in CA1 and CA4, whereas CA2 and dentate granule cells appear to be more resistant. Another important feature in these specimens is a dense fibrillary astrogliosis in all segments with prominent neuronal cell loss, resulting in shrinkage and hardening of the tissue. This macroscopic aspect was first described in 1880 and since then has been classified as Ammon's horn sclerosis (AHS) (2). A second group of temporal lobe epilepsy (TLE) patients harbor focal lesions within the mesial temporal lobe that usually do not involve the hippocampal formation. Among these ...

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A selective loss of somatostatin in the hippocampus of patients with temporal lobe epilepsy

Cited by 203 publications

References 51 publications

Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

Somatostatin: An endogenous antiepileptic

Loss of Hilar Mossy Cells in Ammon's Horn Sclerosis

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