Correlations Between Granule Cell Dispersion, Mossy Fiber Sprouting, and Hippocampal Cell Loss in Temporal Lobe Epilepsy

155

102

Hippocampal specimens resected to cure medically intractable temporal lobe epilepsy (TLE) provide a unique possibility to study functional consequences of morphological alterations. One intriguing alteration predominantly observed in cases of hippocampal sclerosis is an uncommon network of granule cells monosynaptically interconnected via aberrant supragranular mossy fibers. We investigated whether granule cell populations in slices from sclerotic and nonsclerotic hippocampi would develop ictaform activity when challenged by low-frequency hilar stimulation in the presence of elevated extracellular potassium concentration (10 and 12 mM) and whether the experimental activity differs according to the presence of aberrant mossy fibers.We found that ictaform activity could be evoked in slices from sclerotic and nonsclerotic hippocampi (27 of 40 slices, 14 of 20 patients; and 11 of 22 slices, 6 of 12 patients, respectively). However, the two patient groups differed with respect to the pattern of ictaform discharges and the potassium concentration mandatory for its induction. Seizure-like events were already induced with 10 mM K ϩ . They exclusively occurred in slices from sclerotic hippocampi, of which 80% displayed stimulus-induced oscillatory population responses (250 -300 Hz). In slices from nonsclerotic hippocampi, atypical negative field potential shifts were predominantly evoked with 12 mM K ϩ . In both groups, the ictaform activity was sensitive to ionotropic glutamate receptor antagonists and lowering of [Ca 2ϩ ] o . Our results show that, in granule cell populations of hippocampal slices from TLE patients, high K ϩ -induced seizure-like activity and ictal spiking coincide with basic electrophysiological abnormalities, hippocampal sclerosis, and mossy fiber sprouting, suggesting that network reorganization could play a crucial role in determining type and threshold of such activity.

Section: Discussionmentioning

confidence: 56%

Stimulus and Potassium-Induced Epileptiform Activity in the Human Dentate Gyrus from Patients with and without Hippocampal Sclerosis

Gabriel¹,

Njunting²,

Pomper³

et al. 2004

155

102

“…One of the remarkable features of the p35Ϫ/Ϫ animal is the striking similarity in structural abnormalities observed in the dentate gyrus when compared with many current animal models of mesial temporal lobe epilepsy (Sutula, 1990;Ribak and Dashtipour, 2002) as well as to pathologies observed in human tissue from patients with MTLE (Houser, 1990;Lurton et al, 1998;El Bahh et al, 1999;Thom et al, 2002). These studies have implicated GC dispersion, GC basal dendrites, and MF sprouting as structural features highly correlated to the epileptic phenomenology.…”

Section: Structural and Functional Evidence Of Recurrent Excitationmentioning

confidence: 85%

Physiological and Morphological Characterization of Dentate Granule Cells in the p35 Knock-Out Mouse Hippocampus: Evidence for an Epileptic Circuit

Patel¹,

Wenzel²,

Schwartzkroin³

2004

There is a high correlation between pediatric epilepsies and neuronal migration disorders. What remains unclear is whether there are intrinsic features of the individual dysplastic cells that give rise to heightened seizure susceptibility, or whether these dysplastic cells contribute to seizure activity by establishing abnormal circuits that alter the balance of inhibition and excitation. Mice lacking a functional p35 gene provide an ideal model in which to address these questions, because these knock-out animals not only exhibit aberrant neuronal migration but also demonstrate spontaneous seizures.Extracellular field recordings from hippocampal slices, characterizing the input-output relationship in the dentate, revealed little difference between wild-type and knock-out mice under both normal and elevated extracellular potassium conditions. However, in the presence of the GABA A antagonist bicuculline, p35 knock-out slices, but not wild-type slices, exhibited prolonged depolarizations in response to stimulation of the perforant path. There were no significant differences in the intrinsic properties of dentate granule cells (i.e., input resistance, time constant, action potential generation) from wild-type versus knock-out mice. However, antidromic activation (mossy fiber stimulation) evoked an excitatory synaptic response in over 65% of granule cells from p35 knock-out slices that was never observed in wild-type slices. Ultrastructural analyses identified morphological substrates for this aberrant excitation: recurrent axon collaterals, abnormal basal dendrites, and mossy fiber terminals forming synapses onto the spines of neighboring granule cells. These studies suggest that granule cells in p35 knock-out mice contribute to seizure activity by forming an abnormal excitatory feedback circuit.

“…However, it is important to state that the effects of STEP on excitotoxicity are context specific. Along these lines, area CA2 expresses high levels of STEP (Boulanger et al, 1995); yet, unlike the hilus, it is relatively resistant to excitotoxic cell death (Zhang et al, 1997;El Bahh et al, 1999). Mechanistically, it is not known why CA2 neurons are resistant, although numerous studies have shown that CA2 pyramidal neurons are enriched in an array of receptors and trophic factors (Tucker et al, 1993;Ochiishi et al, 1999;Lein et al, 2005) that may affect excitability and/or provide trophic support and thus decrease susceptibility to excitotoxic stimuli.…”

Section: Discussionmentioning

confidence: 99%

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

Choi¹,

Lin²,

Lee³

et al. 2007

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.