inositol-1-4-5-trisphosphate and Epilepsy

Topics: Calcium Channels; Carrier Proteins; Epilepsy; Humans; Inositol 1,4,5-Trisphosphate; Mutation; Protein Binding; Receptors, GABA-A; Signal Transduction

Cytoplasmic calcium, which acts as a second messenger, is derived not only from outside the cell but also from intracellular stores. A receptor for inositol 1,4,5-trisphosphate (IP3), an intracellular second messenger, is located on these internal calcium stores and functions as a calcium releasing channel. The "type 1" IP3 receptor (IP3R1) is concentrated predominantly in cerebellar Purkinje cells and is also widely present in other neural and peripheral tissues, but many of its physiological roles in these cells are still unclear. We have previously succeeded in obtaining mice with disruption of this IP3R1 gene, in which brain IP3-induced calcium release was almost completely abolished. They were rarely born alive, indicating that IP3R1 has some functions during embryonic development. Animals exhibited severe neurological symptoms, ataxia and epilepsy, and were shown to be deficient in the cerebellar long-term depression. They give us promising clues regarding the physiological roles of calcium release from internal stores and serve as a model for the relevant human disease states.

Topics: Animals; Ataxia; Brain; Calcium; Calcium Channels; Electrophysiology; Epilepsy; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Mice; Mice, Knockout; Phenotype; Receptors, Cytoplasmic and Nuclear

Emotional disturbances, depressive mood, anxiety, aggressive behavior, and memory impairment are the common psychiatric features associated with temporal lobe epilepsy (TLE). The present study was carried out to investigate the role of Bacopa monnieri extract in hippocampus of pilocarpine-induced temporal lobe epileptic rats through the 5-HT(2C) receptor in relation to depression. Our results showed upregulation of 5-HT(2C) receptors with a decreased affinity in hippocampus of pilocarpine-induced epileptic rats. Also, there was an increase in 5-HT(2C) gene expression and inositol triphosphate content in epileptic hippocampus. Carbamazepine and B. monnieri treatments reversed the alterations in 5-HT(2C) receptor binding, gene expression, and inositol triphosphate content in treated epileptic rats as compared to untreated epileptic rats. The forced swim test confirmed the depressive behavior pattern during epilepsy that was nearly completely reversed by B. monnieri treatment.

Topics: Animals; Anticonvulsants; Bacopa; Carbamazepine; Disease Models, Animal; Epilepsy; Ergolines; Hippocampus; Inositol 1,4,5-Trisphosphate; Male; Pilocarpine; Plant Preparations; Protein Binding; Radioligand Assay; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Statistics, Nonparametric; Swimming; Tritium; Up-Regulation

A paroxysmal depolarization shift (PDS) has been suggested to be a hallmark for epileptic activity in partial-onset seizures. By monitoring membrane potentials and currents in pairs of pyramidal neurons and astrocytes with dual patch-clamp recording and exocytosis of vesicles from astrocytes with two-photon laser scanning microscopy in hippocampal slices, we found that infusion of inositol 1,4,5-trisphosphate (IP(3)) into astrocytes by patch pipettes induced astrocytic glutamate release that triggered a transient depolarization (TD) and epileptiform discharges in CA1 pyramidal neurons. The TD is due to a tetrodotoxin (TTX)-insensitive slowly decaying transient inward current (STC). Astrocytic glutamate release simultaneously triggers both the STC in pyramidal neurons and a transport current (TC) in astrocytes. The neuronal STC is mediated by ionotropic glutamate receptors leading to the TD and epileptiform discharges; while the astrocytic TC is a glutamate reuptake current resulting from transporting released glutamate into the patched astrocyte. Fusion of a large vesicle in astrocytes was immediately followed by an astrocytic TC, suggesting that the fused vesicle contains glutamate. Both fusion of large vesicles and astrocytic TCs were blocked by tetanus toxin (TeNT), suggesting that astrocytic glutamate release is via SNARE-dependent exocytosis of glutamate-containing vesicles. In the presence of TTX, the epileptogenic reagent, 4-AP, also induced similar neuronal STCs and astrocytic TCs, suggesting that astrocytic glutamate release may play an epileptogenic role in initiation of epileptic seizures under pathological conditions. Our study provides a novel mechanism, astrocytic release of glutamate, for seizure initiation.

Topics: 2-Amino-5-phosphonovalerate; 4-Aminopyridine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Animals, Newborn; Aspartic Acid; Astrocytes; Calcium; Diagnostic Imaging; Drug Interactions; Electric Stimulation; Epilepsy; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; In Vitro Techniques; Inositol 1,4,5-Trisphosphate; Membrane Potentials; Microscopy, Confocal; Neurons; Neurotoxins; Patch-Clamp Techniques; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Tetanus Toxin; Tetrodotoxin; Time Factors

Most modeling studies of neurons and neuronal networks are based on the assumption that the neurons are isolated from their normal environment. Based on recent experimental data we put forward a model for neurons that incorporates the influence of the surrounding glia (dressed neurons). We predict seizurelike spontaneous oscillations in the absence of stimuli for strong coupling between neurons and astrocytes. Consistent with our predictions, a signature of this enhanced crosstalk, over expression of glutamate receptors in astrocytes, has been observed specifically in epileptic tissue.

Topics: Astrocytes; Calcium; Cell Communication; Epilepsy; Inositol 1,4,5-Trisphosphate; Models, Neurological; Neurons

To elucidate the role of the large conductance calcium-activated potassium channel (BK(Ca) channel) in the production of bursting activity, which is characteristic of convulsions, effects of iberiotoxin (IbTX), a selective blocker of the BK(Ca) channel, on bursting activity, induced by various procedures were examined using primary cultured neurons from the cerebral cortex of mice. IbTX completely inhibited bursting activity induced by pentylenetetrazol (PTZ), caffeine, 1,4,5-inositol triphosphate (IP3) and direct forced increase of intracellular calcium. Inherent spontaneous bursting activity in the cerebral cortical neurons of the El mouse, which shows a high susceptibility to convulsions was also completely inhibited by IbTX. Apamin, a specific blocker of the small conductance calcium-activated potassium channel (SK(Ca) channel) showed no inhibition of bursting activity. These findings suggest that the BK(Ca) channel is essential for the production of bursting activity, and also suggest the possibility of clinical use of blocking agents of the BK(Ca) channel against intractable epilepsy.

Topics: Action Potentials; Animals; Apamin; Caffeine; Calcium; Cells, Cultured; Cerebral Cortex; Epilepsy; Inositol 1,4,5-Trisphosphate; Ion Transport; Large-Conductance Calcium-Activated Potassium Channels; Mice; Mice, Neurologic Mutants; Patch-Clamp Techniques; Pentylenetetrazole; Peptides; Potassium Channels; Potassium Channels, Calcium-Activated; Seizures

The inositol 1,4,5-trisphosphate (InsP3) receptor acts as an InsP3-gated Ca2+ release channel in a variety of cell types. Type 1 InsP3 receptor (IP3R1) is the major neuronal member of the IP3R family in the central nervous system, predominantly enriched in cerebellar Purkinje cells but also concentrated in neurons in the hippocampal CA1 region, caudate-putamen, and cerebral cortex. Here we report that most IP3R1-deficient mice generated by gene targeting die in utero, and born animals have severe ataxia and tonic or tonic-clonic seizures and die by the weaning period. An electroencephalogram showed that they suffer from epilepsy, indicating that IP3R1 is essential for proper brain function. However, observation by light microscope of the haematoxylin-eosin staining of the brain and peripheral tissues of IP3R1-deficient mice showed no abnormality, and the unique electrophysiological properties of the cerebellar Purkinje cells of IP3R1-deficient mice were not severely impaired.

Topics: Animals; Ataxia; Base Sequence; Brain; Calcium Channels; Cell Line; DNA Primers; Electroencephalography; Epilepsy; Fetal Death; Gene Targeting; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Mice; Molecular Sequence Data; Mutation; Purkinje Cells; Receptors, Cytoplasmic and Nuclear

Myo-inositol-1,4,5-triphosphoric acid (IP3) formation stimulated by (+-)-1-amino-1,3-cyclopentane-trans-dicarboxylic acid (trans-ACPD) was examined in the cortex, hippocampus and cerebellum of iron-induced epileptic rats and epileptic El mice. Increased IP3 formation by trans-ACPD was observed in the cortex, hippocampus and cerebellum of iron-injected rats while it was found in the hippocampus and cerebellum of the saline-injected control rats. Increased IP3 formation by trans-ACPD was remarkably higher in the hippocampus of iron-injected rats than the other regions. Increased IP3 formation by trans-ACPD was observed in the cortex, hippocampus and cerebellum of ddY mice, while such an increase was found only in the cerebral cortex and not in the hippocampus and cerebellum of El mice. These findings suggest that the inositol response may be involved in the seizure mechanisms of iron-induced epileptic rats and epileptic El mice in some different forms.

Topics: Animals; Brain; Chlorides; Cycloleucine; Disease Models, Animal; Epilepsy; Ferric Compounds; Inositol 1,4,5-Trisphosphate; Male; Mice; Neurotoxins; Rats; Rats, Sprague-Dawley