Subicular Pyramidal Neurons: A Key to Unlock the “Black Box” of Drug Resistance in Temporal Lobe Epilepsy

Object Hippocampal sclerosis can be identified in most patients with mesial temporal lobe epilepsy (TLE). Surgical removal of the sclerotic hippocampus is widely performed to treat patients with drug-resistant mesial TLE. In general, both epilepsy-prone and epilepsy-resistant neurons are believed to be in the hippocampal formation. The hilar mossy cells of the hippocampal dentate gyrus are usually considered one of the most vulnerable types of neurons. The aim of this study was to clarify the fate of mossy cells in the hippocampus in epileptic humans. Methods Of the 19 patients included in this study, 15 underwent temporal lobe resection because of drug-resistant TLE. Four patients were used as controls because they harbored tumors that had not invaded the hippocampus and they had experienced no seizures. Histological evaluation of resected hippocampal tissues was performed using immunohistochemistry. Results Mossy cells were identified in the control as well as the epileptic hippocampi by using cocaine- and amphetamine-regulated transcript peptide immunohistochemistry. In most cases the number of mossy cells was reduced and thorny excrescences were smaller in the epileptic hippocampi than in controls; however, there was a significant loss of pyramidal cells and a partial loss of granule cells in the same epileptic hippocampi in which mossy cell loss was apparent. The loss of mossy cells could be correlated with the extent of hippocampal sclerosis, patient age at seizure onset, duration of epilepsy, and frequency of seizures. Conclusions In many cases large numbers of mossy cells were present in the hilus of the dentate gyrus when most pyramidal neurons of the CA1 and CA3 areas of the Ammon's horn were lost, suggesting that mossy cells may not be more vulnerable to epileptic seizures than the hippocampal pyramidal neurons.

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Corrigendum to “Major vault protein (MVP) gene polymorphisms and drug resistance in mesial temporal lobe epilepsy with hippocampal sclerosis” [Gene 526 (2013) 449–453]

Gene ◽

10.1016/j.gene.2013.09.061 ◽

2013 ◽

Vol 532 (1) ◽

pp. 163

Author(s):

Shabeesh Balan ◽

Saradalekshmi Koramannil Radha ◽

Sanish Sathyan ◽

Joseph Vijai ◽

Moinak Banerjee ◽

...

Keyword(s):

Drug Resistance ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Gene Polymorphisms ◽

Hippocampal Sclerosis ◽

Mesial Temporal Lobe Epilepsy ◽

Major Vault Protein ◽

Mesial Temporal Lobe

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Evaluation of serum ghrelin, nesfatin-1, irisin, and vasoactive intestinal peptide levels in temporal lobe epilepsy patients with and without drug resistance: a cross-sectional study

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.67.02.20200521 ◽

2021 ◽

Vol 67 (2) ◽

pp. 207-212

Author(s):

Ozlem Ergul Erkec ◽

Aysel Milanlıoğlu ◽

Ahmet Ufuk Komuroglu ◽

Mehmet Kara ◽

Zubeyir Huyut ◽

...

Keyword(s):

Drug Resistance ◽

Temporal Lobe Epilepsy ◽

Vasoactive Intestinal Peptide ◽

Temporal Lobe ◽

Cross Sectional Study ◽

Sectional Study ◽

Cross Sectional ◽

Serum Ghrelin

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Metabolomic analysis of blood plasma from patients with mesial temporal lobe epilepsy: a search for biomarkers of drug resistance

10.20396/revpibic2720192701 ◽

2019 ◽

Author(s):

Alexandre de Godoi ◽

◽

Iscia Cendes ◽

Amanda do Canto ◽

Amanda Donatti ◽

...

Keyword(s):

Drug Resistance ◽

Temporal Lobe Epilepsy ◽

Blood Plasma ◽

Temporal Lobe ◽

Mesial Temporal Lobe Epilepsy ◽

Metabolomic Analysis ◽

Mesial Temporal Lobe

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The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy

Neurobiology of Disease ◽

10.1016/j.nbd.2006.06.014 ◽

2006 ◽

Vol 24 (1) ◽

pp. 202-211 ◽

Cited By ~ 165

Author(s):

Claudia Brandt ◽

Kerstin Bethmann ◽

Alexandra M. Gastens ◽

Wolfgang Löscher

Keyword(s):

Drug Resistance ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Rat Model ◽

Multidrug Transporter ◽

Proof Of Principle

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Temporal lobe epilepsy: Evaluation of central and systemic immune-inflammatory features associated with drug resistance.

Seizure ◽

10.1016/j.seizure.2021.07.028 ◽

2021 ◽

Author(s):

Andrea Toledo ◽

Sandra Orozco-Suárez ◽

Marcos Rosetti ◽

Lorenzo Maldonado ◽

Sara I. Bautista ◽

...

Keyword(s):

Drug Resistance ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe

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Major vault protein (MVP) gene polymorphisms and drug resistance in mesial temporal lobe epilepsy with hippocampal sclerosis

Gene ◽

10.1016/j.gene.2013.05.067 ◽

2013 ◽

Vol 526 (2) ◽

pp. 449-453 ◽

Cited By ~ 10

Author(s):

Shabeesh Balan ◽

Sarada lekshmi ◽

Koramannil Radha ◽

Sanish Sathyan ◽

Joseph Vijai ◽

...

Keyword(s):

Drug Resistance ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Gene Polymorphisms ◽

Hippocampal Sclerosis ◽

Mesial Temporal Lobe Epilepsy ◽

Major Vault Protein ◽

Mesial Temporal Lobe

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Ca2+-Dependent Inactivation of High-Threshold Ca2+ Currents in Hippocampal Granule Cells of Patients With Chronic Temporal Lobe Epilepsy

Journal of Neurophysiology ◽

10.1152/jn.1999.82.2.946 ◽

1999 ◽

Vol 82 (2) ◽

pp. 946-954 ◽

Cited By ~ 15

Author(s):

Heinz Beck ◽

Ralf Steffens ◽

Uwe Heinemann ◽

Christian E. Elger

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Pyramidal Neurons ◽

Granule Cells ◽

Feedback Mechanism ◽

Calcium Currents ◽

High Threshold ◽

Kindling Model ◽

Dependent Inactivation ◽

Intracellular Ca

Intracellular Ca2+ represents an important trigger for various second-messenger mediated effects. Therefore a stringent control of the intracellular Ca2+ concentration is necessary to avoid excessive activation of Ca2+-dependent processes. Ca2+-dependent inactivation of voltage-dependent calcium currents (VCCs) represents an important negative feedback mechanism to limit the influx of Ca2+ that has been shown to be altered in the kindling model of epilepsy. We therefore investigated the Ca2+-dependent inactivation of high-threshold VCCs in dentate granule cells (DGCs) isolated from the hippocampus of patients with drug-refractory temporal lobe epilepsy (TLE) using the patch-clamp method. Ca2+ currents showed pronounced time-dependent inactivation when no extrinsic Ca2+ buffer was present in the patch pipette. In addition, in double-pulse experiments, Ca2+ entry during conditioning prepulses caused a reduction of VCC amplitudes elicited during a subsequent test pulse. Recovery from Ca2+-dependent inactivation was slow and only complete after 1 s. Ca2+-dependent inactivation could be blocked either by using Ba2+ as a charge carrier or by including bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid (BAPTA) or EGTA in the intracellular solution. The influence of the cytoskeleton on Ca2+-dependent inactivation was investigated with agents that stabilize and destabilize microfilaments or microtubules, respectively. From these experiments, we conclude that Ca2+-dependent inactivation in human DGCs involves Ca2+-dependent destabilization of both microfilaments and microtubules. In addition, the microtubule-dependent pathway is modulated by the intracellular concentration of GTP, with lower concentrations of guanosine triphosphate (GTP) causing increased Ca2+-dependent inactivation. Under low-GTP conditions, the amount of Ca2+-dependent inactivation was similar to that observed in the kindling model. In summary, Ca2+-dependent inactivation was present in patients with TLE and Ammon’s horn sclerosis (AHS) and is mediated by the cytoskeleton similar to rat pyramidal neurons. The similarity to the kindling model of epilepsy may suggest the possibility of altered Ca2+-dependent inactivation in patients with AHS.

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