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Robert J DeLorenzo

Publications and source records attributed to Robert J DeLorenzo.

17 recordsLinked to original sources
PubMed2006

Endocannabinoids block status epilepticus in cultured hippocampal neurons.

Status epilepticus is a serious neurological disorder associated with a significant morbidity and mortality. Antiepileptic drugs such as diazepam, phenobarbital and phenytoin are the mainstay of status epilepticus treatment. However, over 20% of status epilepticus cases are refractory to the initial treatment with two or more antiepileptic drugs. Endocannabinoids have been implicated as playing an important role in regulating seizure activity and seizure termination. This study evaluated the effects of the major endocannabinoids methanandamide and 2-arachidonylglycerol (2-AG) on status epilepticus in the low-Mg(2+) hippocampal neuronal culture model. Status epilepticus in this model was resistant to treatment with phenobarbital and phenytoin. Methanandamide and 2-AG inhibited status epilepticus in a dose-dependent manner with an EC(50) of 145+/-4.15 nM and 1.68+/-0.19 microM, respectively. In addition, the anti-status epilepticus effects of methanandamide and 2-AG were mediated by activation of the cannabinoid CB(1) receptor since they were blocked by the cannabinoid CB(1) receptor antagonist AM251. These results provide the first evidence that the endocannabinoids, methanandamide and 2-AG, are effective inhibitors of refractory status epilepticus in the hippocampal neuronal culture model and indicate that regulating the endocannabinoid system may provide a novel therapeutic approach for treating refractory status epilepticus.

Animals↗
PubMed2006

Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy.

Status epilepticus (SE) is a major medical emergency associated with a significant morbidity and mortality. Little is known about the mechanisms that terminate seizure activity and prevent the development of status epilepticus. Cannabinoids possess anticonvulsant properties and the endocannabinoid system has been implicated in regulating seizure duration and frequency. Endocannabinoids regulate synaptic transmission and dampen seizure activity via activation of the presynaptic cannabinoid receptor 1 (CB1). This study was initiated to evaluate the role of CB1 receptor-dependent endocannabinoid synaptic transmission towards preventing the development of status epilepticus-like activity in the well-characterized hippocampal neuronal culture model of acquired epilepsy using patch clamp electrophysiology. Application of the CB1 receptor antagonists SR141716A (1 microM) or AM251 (1 microM) to "epileptic" neurons caused the development of continuous epileptiform activity, resembling electrographic status epilepticus. The induction of status epilepticus-like activity by CB1 receptor antagonists was reversible and could be overcome by maximal concentrations of CB1 agonists. Similar treatment of control neurons with CB1 receptor antagonists did not produce status epilepticus or hyperexcitability. These findings suggest that CB1 receptor-dependent endocannabinoid endogenous tone plays an important role in modulating seizure frequency and duration and preventing the development of status epilepticus-like activity in populations of epileptic neurons. The regulation of seizure activity and prevention of status epilepticus by the endocannabinoid system offers an important insight into understanding the basic mechanisms that control the development of continuous epileptiform discharges.

Action Potentials↗
PubMed2006

Altered calcium/calmodulin kinase II activity changes calcium homeostasis that underlies epileptiform activity in hippocampal neurons in culture.

Epilepsy is characterized by the occurrence of spontaneous recurrent epileptiform discharges (SREDs) in neurons. A decrease in calcium/calmodulin-dependent protein kinase II (CaMK-II) activity has been shown to occur with the development of SREDs in a hippocampal neuronal culture model of acquired epilepsy, and altered calcium (Ca(2+)) homeostasis has been implicated in the development of SREDs. Using antisense oligonucleotides, this study was conducted to determine whether selective suppression of CaMK-II activity, with subsequent induction of SREDs, was associated with altered Ca(2+) homeostasis in hippocampal neurons in culture. Antisense knockdown resulted in the development of SREDs and a decrease in both immunocytochemical staining and enzyme activity of CaMK-II. Evaluation of [Ca(2+)](i) using Fura indicators revealed that antisense-treated neurons manifested increased basal [Ca(2+)](i), whereas missense-treated neurons showed no change in basal [Ca(2+)](i). Antisense suppression of CaMK-II was also associated with an inability of neurons to restore a Ca(2+) load. Upon removal of oligonucleotide treatment, CaMK-II suppression and Ca(2+) homeostasis recovered to control levels and SREDs were abolished. To our knowledge, the results demonstrate the first evidence that selective suppression of CaMK-II activity results in alterations in Ca(2+) homeostasis and the development of SREDs in hippocampal neurons and suggest that CaMK-II suppression may be causing epileptogenesis by altering Ca(2+) homeostatic mechanisms.

Algorithms↗
PubMed2006

Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus.

Cannabinoids have been shown to have anticonvulsant properties, but no studies have evaluated the effects of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy (AE) and status epilepticus (SE). This study investigated the anticonvulsant properties of the cannabinoid receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolol[1,2,3 de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone (WIN 55,212-2) in primary hippocampal neuronal culture models of both AE and SE. WIN 55,212-2 produced dose-dependent anticonvulsant effects against both spontaneous recurrent epileptiform discharges (SRED) (EC50 = 0.85 microM) and SE (EC50 = 1.51 microM), with total suppression of seizure activity at 3 microM and of SE activity at 5 microM. The anticonvulsant properties of WIN 55,212-2 in these preparations were both stereospecific and blocked by the cannabinoid type-1 (CB1) receptor antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A; 1 microM), showing a CB1 receptor-dependent pathway. The inhibitory effect of WIN 55,212-2 against low Mg2+-induced SE is the first observation in this model of total suppression of SE by a selective pharmacological agent. The clinically used anticonvulsants phenytoin and phenobarbital were not able to abolish low Mg2+-induced SE at concentrations up to 150 microM. The results from this study show CB1 receptor-mediated anticonvulsant effects of the cannabimimetic WIN 55,212-2 against both SRED and low Mg2+-induced SE in primary hippocampal neuronal cultures and show that these in vitro models of AE and SE may represent powerful tools to investigate the molecular mechanisms mediating the effects of cannabinoids on neuronal excitability.

Animals↗
PubMed2006

Erratum to "Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintenance of epilepsy." [Pharmacol. Ther. 105(3) (2005) 229-266].

Epilepsy is one of the most common neurological disorders. Although epilepsy can be idiopathic, it is estimated that up to 50% of all epilepsy cases are initiated by neurological insults and are called acquired epilepsy (AE). AE develops in 3 phases: (1) the injury [central nervous system (CNS) insult]. (2) epileptogenesis (latency), and (3) the chronic epileptic (spontaneous recurrent seizure) phases. Status epilepticus (SE), stroke, and traumatic brain injury (TBI) are 3 major examples of common brain injuries that can lead to the development of AE. It is especially important to understand the molecular mechanisms that cause AE because it may lead to innovative strategies to prevent or cure this common condition. Recent studies have offered new insights into the cause of AE and indicate that injury-induced alterations in intracellular calcium concentration levels ([Ca(2+)](i)) and calcium homeostatic mechanisms play a role in the development and maintenance of AE. The injuries that cause AE are different, but the share a common molecular mechanism for producing brain damage--an increase in extracellular glutamate and are exposed to increased [Ca(2+)](i) are the cellular substrates to develop epilepsy because dead cells do not seize. The neurons that survive injury sustain permanent long-term plasticity changes in [Ca(2+)](i) and calcium homeostatic mechanisms that are permanent and are a prominent feature of the epileptic phenotype. In the last several years, evidence has accumulated indicating that the prolonged alteration in neuronal calcium dynamics plays an important role in the induction and maintenance of the prolonged neuroplasticity changes underlying the epileptic phenotype. Understanding the role of calcium as a second messenger in the induction and maintenance of epilepsy may provide novel insights into therapeutic advances that will prevent and even cure AE.

Animals↗
PubMed2005

Basic research in epilepsy and aging.

A PubMed search of the years 1965 to 2003 found only 30 articles that were directly related to modeling seizures or epilepsy in aged animals. This lack of research is disturbing but explainable because of the high cost of aged animals and their increasing infirmity. Many changes occur in the older brain: cell loss in the hippocampal formation, changes in long-term potentiation maintenance, alteration in kindling, increased susceptibility to status epilepticus, and neuronal damage from stroke. The effect of aging on voltage-gated sodium and calcium channels has not been studied sufficiently. With increasing numbers of elderly persons with epilepsy needing appropriate treatment, the need to better understand the basic mechanisms of epilepsy is crucial.

Aged↗
PubMed2004

Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy.

Alterations in hippocampal neuronal Ca(2+) and Ca(2+)-dependent systems have been implicated in mediating some of the long-term neuroplasticity changes associated with acquired epilepsy (AE). However, there are no studies in an animal model of AE that directly evaluate alterations in intracellular calcium concentration ([Ca(2+)](i)) and Ca(2+) homeostatic mechanisms (Ca(2+) dynamics) during the development of AE. In this study, Ca(2+) dynamics were evaluated in acutely isolated rat CA1 hippocampal, frontal, and occipital neurons in the pilocarpine model by using [Ca(2+)](i) imaging fluorescence microscopy during the injury (acute), epileptogenesis (latency), and chronic-epilepsy phases of the development of AE. Immediately after status epilepticus (SE), hippocampal neurons, but not frontal and occipital neurons, had significantly elevated [Ca(2+)](i) compared with saline-injected control animals. Hippocampal neuronal [Ca(2+)](i) remained markedly elevated during epileptogenesis and was still elevated indefinitely in the chronic-epilepsy phase but was not elevated in SE animals that did not develop AE. Inhibiting the increase in [Ca(2+)](i) during SE with the NMDA channel inhibitor MK801 was associated in all three phases of AE with inhibition of the changes in Ca(2+) dynamics and the development of AE. Ca(2+) homeostatic mechanisms in hippocampal neurons also were altered in the brain-injury, epileptogenesis, and chronic-epilepsy phases of AE. These results provide evidence that [Ca(2+)](i) and Ca(2+)-homeostatic mechanisms are significantly altered during the development of AE and suggest that altered Ca(2+) dynamics may play a role in the induction and maintenance of AE and underlie some of the neuroplasticity changes associated with the epileptic phenotype.

Animals↗
PubMed2004

Neuronal-specific endoplasmic reticulum Mg(2+)/Ca(2+) ATPase Ca(2+) sequestration in mixed primary hippocampal culture homogenates.

Endoplasmic reticulum Mg(2+)/Ca(2+) ATPase Ca(2+) sequestration is crucial for maintenance of neuronal Ca(2+) homeostasis. The use of cell culture in conjunction with modern Ca(2+) imaging techniques has been invaluable in elucidating these mechanisms. While imaging protocols evaluate endoplasmic reticulum Ca(2+) loads, measurement of Mg(2+)/Ca(2+) ATPase activity is indirect, comparing cytosolic Ca(2+) levels in the presence or absence of the Mg(2+)/Ca(2+) ATPase inhibitor thapsigargin. Direct measurement of Mg(2+)/Ca(2+) ATPase by isolation of microsomes is impossible due to the minuscule amounts of protein yielded from cultures used for imaging. In the current study, endoplasmic reticulum Mg(2+)/Ca(2+) ATPase Ca(2+) sequestration was measured in mixed homogenates of neurons and glia from primary hippocampal cultures. It was demonstrated that Ca(2+) uptake was mediated by the endoplasmic reticulum Mg(2+)/Ca(2+) ATPase due to its dependence on ATP and Mg(2+), enhancement by oxalate, and inhibition by thapsigargin. It was also shown that neuronal Ca(2+) uptake, mediated by the type 2 sarco(endo)plasmic reticulum Ca(2+) ATPase isoform, could be distinguished from glial Ca(2+) uptake in homogenates composed of neurons and glia. Finally, it was revealed that Ca(2+) uptake was sensitive to incubation on ice, extremely labile in the absence of protease inhibitors, and significantly more stable under storage conditions at -80 degrees C.

Animals↗
PubMed2004

Epileptogenesis causes acute and chronic increases in GABAA receptor endocytosis that contributes to the induction and maintenance of seizures in the hippocampal culture model of acquired epilepsy.

Altered GABAergic inhibitory tone has been observed in association with a number of both acute and chronic models of epilepsy and is believed to be the result, in part, of a decrease in function of the postsynaptic GABAA receptor (GABAAR). This study was carried out to investigate if alterations in receptor internalization contribute to the decrease in GABAAR function observed with epilepsy, utilizing the hippocampal neuronal culture model of low-Mg2+-induced spontaneous recurrent epileptiform discharges (SREDs). Analysis of GABAAR function in "epileptic" cultures showed a 62% reduction in [3H]flunitrazepam binding to the GABAA alpha receptor subunit and a 50% decrease in GABA currents when compared with controls. Confocal microscopy analysis of immunohistochemical staining of GABAAR beta2/beta3 subunit expression revealed approximately a 30% decrease of membrane staining in hippocampal cultures displaying SREDs immediately after low-Mg2+ treatment and in the chronic epileptic state. Low-Mg2+-treated cultures internalized antibody labeled GABAA receptor with an increase in rate of 68% from control. Inhibition of GABAAR endocytosis in epileptic cultures resulted in both a recovery to control levels of membrane GABAA beta2/beta3 immunostaining and a total blockade of SREDs. These results indicate that altered GABAAR endocytosis contributes to the decrease in GABAAR expression and function observed in this in vitro model of epilepsy and plays a role in causing and maintaining SREDs. Understanding the mechanisms underlying altered GABAA R recycling may offer new insights into the pathophysiology of epilepsy and provide novel therapeutic strategies to treat this major neurological condition.

Animals↗
PubMed2004

Long-lasting alterations in neuronal calcium homeostasis in an in vitro model of stroke-induced epilepsy.

Altered calcium homeostatic mechanisms have been implicated in the development of acquired epilepsy in numerous models. Stroke is one of the leading brain injuries that cause acquired epilepsy, yet little is known concerning the molecular mechanisms underlying stroke-induced epileptogenesis. Recently an in vitro model of stroke-induced epilepsy was developed and characterized as a powerful tool to study the pathophysiology of injury and stroke-induced epileptogenesis. Using this glutamate injury-induced epileptogenesis model, we have investigated the role of altered calcium homeostatic mechanisms in the development and maintenance of stroke-induced epilepsy. Epileptic neurons manifested elevated intracellular calcium levels compared to control neurons independent of neuronal activity and seizure discharge for the remainder of the life of the neurons in culture. In addition, epileptic neurons were found to have alterations in the ability to reduce intracellular calcium levels following a calcium load. These long-term epileptic changes in calcium homeostasis were dependent on calcium during the initial glutamate injury. The data demonstrate that significant alterations in calcium homeostatic mechanisms occur in association with stroke-induced epilepsy and suggest that these changes may play a role in both the induction and maintenance of the epileptic phenotype in this model.

Animals↗
PubMed2004

Status epilepticus in a population-based Virginia twin sample.

PURPOSE: To characterize status epilepticus (SE) and estimate its frequency of first occurrence, as well as to assess the contribution of genetic factors to risk of SE occurrence in a sample of Virginia-born twins ascertained from the population-based Mid-Atlantic Twin Registry. METHODS: The occurrence of SE was determined in 13,506 unselected Virginia-born twin pairs ascertained from birth records. Twins included in the study were between ages 2 and 75 years when surveyed. History of seizures and SE was validated through medical records and by detailed personal or parental interviews. RESULTS: Among 381 twins included in 332 pairs with a verified history of seizures, 70 (18.4%) were validated to have had at least one episode of SE. The frequency of first SE in this sample was 309 per 100,000 twins. First SE occurred in conjunction with 21 of 158 febrile and 49 of 223 afebrile seizure cases, respectively. Mean length of SE episode was 76.2 +/- 14.9 min. Age at first SE occurrence ranged from 2 months to 59 years. All concordant twin pairs in the sample were monozygotic (MZ), with a proband-wise concordance rate estimated for SE in this population of 0.31 [95% confidence interval (CI), 0.14-0.52) overall, and 0.67 (95% CI, 0.35-0.90) in pairs concordant for epilepsy. CONCLUSIONS: These results provide a direct estimate of the frequency of SE in a defined population of twins and afford further evidence for a genetic contribution to risk for SE.

Adolescent↗
PubMed2003

The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy.

Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Delta9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus. Furthermore, we determined that during an short-term pilocarpine-induced seizure, levels of the endogenous CB1 ligand 2-arachidonylglycerol increased significantly within the hippocampal brain region. These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was significantly increased throughout the CA regions of epileptic hippocampi. By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.

Animals↗
PubMed2003

Induction of prolonged electrographic seizures in vitro has a defined threshold and is all or none: implications for diagnosis of status epilepticus.

PURPOSE: To study whether induction of prolonged (>30-min duration) in vitro electrographic seizure discharges resembling status epilepticus (SE) is graded or all-or-none, and to determine the critical factors mediating SE induction. METHODS: Prolonged electrographic seizure discharges were induced in combined hippocampal-entorhinal cortical (HEC) brain slices by electrical stimulation of the Schaeffer collaterals. Discharges were recorded by using field-potential electrodes in the dentate gyrus, CA3, CA1, and entorhinal cortex. Slices were prepared from rats that were (a). 21- to 30-day-old naive, (b). 60- to 120-day old naive, (c). epileptic, and (d). status post a prior traumatic brain injury. RESULTS: Induction of SE discharges was dependent on the duration, but not amplitude of the preceding stimulus train-induced afterdischarge in HEC slices from 21- to 30-day-old control, brain-injured, and epileptic animals, but not from 60- to 120-day-old animals. In slices from 21- to 30-day-old control animals, once afterdischarges exceeded 4 min in duration, SE was induced in 50% of slices, and after >or=6 min 37 s seizure activity; SE was induced in 95% of slices. A defined SE threshold also was evident in brain-damaged rats, including rats in which an epileptic condition was induced by pilocarpine injection 4-16 weeks before recording, and rats subjected to a fluid percussive head trauma 1-8 weeks before recording. However, in these brain-damaged animals, mean SE threshold was considerably lower (24 and 44 s, respectively). HEC slices from 60- to 120-day-old controls for the brain-injured and epileptic animals did not develop SE even after 20 stimulations, demonstrating the pronounced effect of brain injury and epilepsy on the development of SE in the HEC slice preparation compared with that in age-matched controls. CONCLUSIONS: In vitro, SE discharges have a defined temporal threshold for initiation. Once a seizure exceeds 6-7 min in duration in control animals, and 30-55 s in brain-damaged animals, the probability of SE induction is greatly increased. This demonstrates that brain injury lowers the afterdischarge duration required to produce SE and suggests that brains injured from trauma or SE are more susceptible to develop status epilepticus.

Animals↗
PubMed2002

Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity.

The anticonvulsant effect of cannabinoids has been shown to be mediated through activation of the cannabinoid CB(1) receptor. This study was initiated to evaluate the effects of endogenously occurring cannabinoids (endocannabinoids) on seizure severity and threshold. The anticonvulsant effect of the endocannabinoid, arachidonylethanolamine (anandamide), was evaluated in the maximal electroshock seizure model using male CF-1 mice and was found to be a fully efficacious anticonvulsant (ED(50)=50 mg/kg i.p.). The metabolically stable analog of anandamide, (R)-(20-cyano-16,16-dimetyldocosa-cis-5,8,11,14-tetraenoyl)-1'-hydroxy-2'-propylamine (O-1812), was also determined to be a potent anticonvulsant in the maximal electroshock model (ED(50)=1.5 mg/kg i.p.). Furthermore, pretreatment with the cannabinoid CB(1) receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) completely abolished the anticonvulsant effect of anandamide as well as O-1812 (P< or =0.01, Fisher exact test), indicating a cannabinoid CB(1) receptor-mediated anticonvulsant mechanism for both endocannabinoid compounds. Additionally, the influence of cannabinoid CB(1) receptor endogenous tone on maximal seizure threshold was assessed using SR141716A alone. Our data show that SR141716A (10 mg/kg i.p.) significantly reduced maximal seizure threshold (CC(50)=14.27 mA) compared to vehicle-treated animals (CC(50)=17.57 mA) (potency ratio=1.23, lower confidence limit=1.06, upper confidence limit=1.43), indicating the presence of an endogenous cannabinoid tone that modulates seizure activity. These data demonstrate that anandamide and its analog, O-1812, are anticonvulsant in a whole animal model and further implicate the cannabinoid CB(1) receptor as a major endogenous site of seizure modulation.

Animals↗
PubMed2002

Calcium-dependent epileptogenesis in an in vitro model of stroke-induced "epilepsy".

PURPOSE: Stroke is the most common cause of acquired epilepsy. The purpose of this investigation was to characterize the role of calcium in the in vitro, glutamate injury-induced epileptogenesis model of stoke-induced epilepsy. METHODS: Fura-2 calcium imaging and whole-cell current clamp electrophysiology techniques were used to measure short-term changes in neuronal free intracellular calcium concentration and long-term alterations in neuronal excitability in response to epileptogenic glutamate injury (20 microM, 10 min) under various extracellular calcium conditions and in the presence of different glutamate-receptor antagonists. RESULTS: Glutamate injury-induced epileptogenesis was associated with prolonged, reversible elevations of free intracellular calcium concentration during and immediately after injury and chronic hyperexcitability manifested as spontaneous recurrent epileptiform discharges for the remaining life of the cultures. Epileptogenic glutamate exposure performed in solutions containing low extracellular calcium, barium substituted for calcium, or N-methyl-d-aspartate (NMDA)-receptor antagonists reduced the duration of intracellular calcium elevation and inhibited epileptogenesis. Antagonism of non-NMDA-receptor subtypes had no effect on glutamate injury-induced calcium changes or the induction epileptogenesis. The duration of the calcium elevation and the total calcium load statistically correlated with the development of epileptogenesis. Comparable elevations in neuronal calcium induced by non-glutamate receptor-mediated pathways did not cause epileptogenesis. CONCLUSIONS: This investigation indicates that the glutamate injury-induced epileptogenesis model of stroke-induced epilepsy is calcium dependent and requires NMDA-receptor activation. Further, these experiments suggest that prolonged, reversible elevations in neuronal free intracellular calcium initiate the long-term plasticity changes that underlie the development of injury-induced epilepsy.

Animals↗