Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy

Proper, E.A.; Oestreicher, A.B.; Jansen, Gerard H.; Veelen, C.W.M. van; Rijen, Peter C. van; Gispen, W.H.; Graan, P.N.E. de

doi:10.1093/brain/123.1.19

Cited by 142 publications

(128 citation statements)

References 33 publications

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“…However, our data showed significant increases in GFAP in epileptic hippocampus (two-fold) and neocortex (1.7-fold) when compared with their controls. Our results on GFAP agree with previous studies which reported that glial cells are activated during seizures in temporal lobe epilepsy, leading to increased GFAP levels and astrogliosis (Taniwaki et al 1996;Proper et al 2000;Aronica et al 2001). These results showing that b-actin and a specific marker of neurons do not decrease in epileptic tissues despite the fact that epileptic patients showed neuronal loss associated with hippocampal sclerosis strongly indicate the existence of compensatory mechanisms by the remaining neurons and/or other cell types, such as glial cells, in the hippocampus in agreement with previous reports (Hansen et al 1990;DeGiorgio et al 1996).…”

Section: Down-regulation Of Pimt In the Hippocampus Of Epileptic Patisupporting

confidence: 92%

Down‐regulation of protein l‐isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin

Lanthier

Bouthillier

Lapointe

et al. 2002

Journal of Neurochemistry

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Protein L-isoaspartyl methyltransferase (PIMT) repairs the damaged proteins which have accumulated abnormal aspartyl residues during cell aging. Gene targeting has elucidated a physiological role for PIMT by showing that mice lacking PIMT died prematurely from fatal epileptic seizures. Here we investigated the role of PIMT in human mesial temporal lobe epilepsy. Using surgical specimens of hippocampus and neocortex from controls and epileptic patients, we showed that PIMT activity and expression were 50% lower in epileptic hippocampus than in controls but were unchanged in neocortex. Although the protein was down-regulated, PIMT mRNA expression was unchanged in epileptic hippocampus, suggesting post-translational regulation of the PIMT level. Moreover, several proteins with abnormal aspartyl residues accumulate in epileptic hippocampus. Microtubules component b-tubulin, one of the major PIMT substrates, had an increased amount (two-fold) of L-isoaspartyl residues in the epileptic hippocampus. These results demonstrate that the down-regulation of PIMT in epileptic hippocampus leads to a significant accumulation of damaged tubulin that could contribute to neuron dysfunction in human mesial temporal lobe epilepsy.

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Section: Down-regulation Of Pimt In the Hippocampus Of Epileptic Patisupporting

confidence: 92%

Down‐regulation of protein l‐isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin

Lanthier

Bouthillier

Lapointe

et al. 2002

Journal of Neurochemistry

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“…46). Moreover, sprouting of mossy fibers, observed in several animal models of epilepsy (41) and epileptic patients (47), has been proposed to induce increased excitability of hippocampal circuitry and promote epileptogenesis (42). Galanin is not normally expressed in dentate granule cells and mossy fibers (2,6,48).…”

Section: Resultsmentioning

confidence: 99%

Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin

Kokaia

Holmberg

Nanobashvili

et al. 2001

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

101

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The neuropeptide galanin has been shown to suppress epileptic seizures. In cortical and hippocampal areas, galanin is normally mainly expressed in noradrenergic afferents. We have generated a mouse overexpressing galanin in neurons under the plateletderived growth factor B promoter. RIA and HPLC analysis revealed up to 8-fold higher levels of galanin in transgenic as compared with wild-type mice. Ectopic galanin overexpression was detected especially in dentate granule cells and hippocampal and cortical pyramidal neurons. Galanin-overexpressing mice showed retardation of seizure generalization during hippocampal kindling, a model for human complex partial epilepsy. The high levels of galanin in mossy fibers found in the transgenic mice were further increased after seizures. Frequency facilitation of field excitatory postsynaptic potentials, a form of short-term synaptic plasticity assessed in hippocampal slices, was reduced in mossy fiber-CA3 cell synapses of galanin-overexpressing mice, indicating suppressed glutamate release. This effect was reversed by application of the putative galanin receptor antagonist M35. These data provide evidence that ectopically overexpressed galanin can be released and dampen the development of epilepsy by means of receptor-mediated action, at least partly by reducing glutamate release from mossy fibers.G alanin, a 29-aa neuropeptide (1), is widely distributed throughout the rat brain (2, 3) and coexists with classic transmitters in several systems (4), with particularly high levels in noradrenergic locus coeruleus neurons (5, 6). Galanin-binding sites have been mapped (7,8), and three receptor subtypes, GalR1 (9-11), 49), and GalR3 (15), have been cloned. There is evidence for involvement of galanin in multiple neuronal functions (16,17), as also revealed in recent studies on transgenic mice (18)(19)(20).Many studies support an important role of neuropeptides in seizure activity (21)(22)(23). This role is true also for galanin. Thus, intrahippocampal injection of galanin during status epilepticus (SE) in rats has powerful anticonvulsant effects (24). In accordance with these data, mice overexpressing the galanin gene under the dopamine-␤-hydroxylase promoter, presumably in noradrenergic fibers, show increased resistance to SE and kainate-and pentylenetetrazol-evoked seizures (25). Conversely, administration of galanin antagonists, such as M35 (26), and targeted disruption of the galanin gene increase seizure susceptibility in these models (24,25). Taken together, available data indicate that galanin released from noradrenergic fibers (3, 5, 27) can suppress epileptic seizures. Although the underlying mechanisms are not known, it has been shown that galanin can inhibit glutamate release by means of activation of presynaptic ATP-dependent K ϩ channels (28).We speculated that galanin release from neurons not normally containing this neuropeptide, e.g., in the epileptic focus, might be necessary to optimize the seizure-suppressant action of galanin. To explore the functional conseque...

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“…In light of this idea, it is understandable that TLE is often chronic and intractable. Expression of PSA-NCAM in the hippocampus is reported to increase in TLE patients (Mikkonen et al, 1998;Proper et al, 2000) and pilocarpine-induced epileptic rats (Shan et al, 2002). This may make the MF ectopia more stubborn.…”

Section: Induction Of Mossy Fiber Sprouting By Abnormal Axon Guidancementioning

confidence: 99%

Mossy Fiber Sprouting as a Potential Therapeutic Target for Epilepsy

Koyama

Ikegaya²

2004

CNR

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Hippocampal mossy fibers, axons of dentate granule cells, converge in the dentate hilus and run through a narrow area called the stratum lucidum to synapse with hilar and CA3 neurons. In the hippocampal formation of temporal lobe epilepsy patients, however, this stereotyped pattern of projection is often collapsed; the mossy fibers branch out of the dentate hilus and abnormally innervate the dentate inner molecular layer, a phenomenon that is termed mossy fiber sprouting. Experimental studies have replicated this sprouting in animal models of temporal lobe epilepsy, including kindling and pharmacological treatment with convulsants. Because these axon collaterals form recurrent excitatory inputs into dendrites of granule cells, the circuit reorganization is assumed to cause epileptiform activity in the hippocampus, whereas some recent studies indicate that the sprouting is not necessarily associated with early-life seizures. Here we review the mechanisms of mossy fiber sprouting and consider its potential contribution to epileptogenesis. Based on recent findings, we propose that the sprouting can be regarded as a result of disruption of the molecular mechanisms underlying the axon guidance. We finally focus on the possibility that prevention of the abnormal sprouting might be a new strategy for medical treatment with temporal lobe epilepsy.

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Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy

Cited by 142 publications

References 33 publications

Down‐regulation of protein l‐isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin

Down‐regulation of protein l‐isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin

Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin

Mossy Fiber Sprouting as a Potential Therapeutic Target for Epilepsy

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