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

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.

Download Full-text

Properties of potassium and calcium currents in dentate granule cells from patients with temporal lobe epilepsy

Electroencephalography and Clinical Neurophysiology ◽

10.1016/s0013-4694(97)88037-x ◽

1997 ◽

Vol 103 (1) ◽

pp. 29

Author(s):

U Heinemann

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Granule Cells ◽

Calcium Currents ◽

Dentate Granule Cells

Download Full-text

Calcium-dependent inactivation of high-threshold calcium currents in human dentate gyrus granule cells

The Journal of Physiology ◽

10.1111/j.1469-7793.1998.039bo.x ◽

1998 ◽

Vol 509 (1) ◽

pp. 39-45 ◽

Cited By ~ 31

Author(s):

U. Valentin Nägerl ◽

Istvan Mody

Keyword(s):

Dentate Gyrus ◽

Granule Cells ◽

Calcium Currents ◽

High Threshold ◽

Calcium Dependent ◽

Dependent Inactivation

Download Full-text

Astrocytic GABA Accumulation in Experimental Temporal Lobe Epilepsy

Frontiers in Neurology ◽

10.3389/fneur.2020.614923 ◽

2020 ◽

Vol 11 ◽

Author(s):

Julia Müller ◽

Aline Timmermann ◽

Lukas Henning ◽

Hendrik Müller ◽

Christian Steinhäuser ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Pyramidal Neurons ◽

Granule Cells ◽

Hippocampal Sclerosis ◽

Tonic Inhibition ◽

Reactive Astrocytes ◽

Ca1 Region ◽

Human Epilepsy ◽

Gaba Accumulation

An imbalance of excitation and inhibition has been associated with the pathophysiology of epilepsy. Loss of GABAergic interneurons and/or synaptic inhibition has been shown in various epilepsy models and in human epilepsy. Despite this loss, several studies reported preserved or increased tonic GABAA receptor-mediated currents in epilepsy, raising the question of the source of the inhibitory transmitter. We used the unilateral intracortical kainate mouse model of temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) to answer this question. In our model we observed profound loss of interneurons in the sclerotic hippocampal CA1 region and dentate gyrus already 5 days after epilepsy induction. Consistent with the literature, the absence of interneurons caused no reduction of tonic inhibition of CA1 pyramidal neurons. In dentate granule cells the inhibitory currents were even increased in epileptic tissue. Intriguingly, immunostaining of brain sections from epileptic mice with antibodies against GABA revealed strong and progressive accumulation of the neurotransmitter in reactive astrocytes. Pharmacological inhibition of the astrocytic GABA transporter GAT3 did not affect tonic inhibition in the sclerotic hippocampus, suggesting that this transporter is not responsible for astrocytic GABA accumulation or release. Immunostaining further indicated that both decarboxylation of glutamate and putrescine degradation accounted for the increased GABA levels in reactive astrocytes. Together, our data provide evidence that the preserved tonic inhibitory currents in the epileptic brain are mediated by GABA overproduction and release from astrocytes. A deeper understanding of the underlying mechanisms may lead to new strategies for antiepileptic drug therapy.

Download Full-text

Survival of mossy cells of the hippocampal dentate gyrus in humans with mesial temporal lobe epilepsy

Journal of Neurosurgery ◽

10.3171/2008.11.jns08779 ◽

2009 ◽

Vol 111 (6) ◽

pp. 1237-1247 ◽

Cited By ~ 17

Author(s):

László Seress ◽

Hajnalka Ábrahám ◽

Zsolt Horváth ◽

Tamás Dóczi ◽

József Janszky ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Pyramidal Neurons ◽

Hippocampal Sclerosis ◽

Mesial Temporal Lobe Epilepsy ◽

Drug Resistant ◽

Hippocampal Dentate Gyrus ◽

Mossy Cells ◽

Mesial Temporal Lobe

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.

Download Full-text