Paroxysmal Depolarization Shifts Research Articles

Participation of calcium-permeable AMPA receptors in the regulation of epileptiform activity of hippocampal neurons.

Epileptiform activity is the most striking result of hyperexcitation of a group of neurons that can occur in different brain regions and then spread to other sites. Later it was shown that these rhythms have a cellular correlate in vitro called paroxysmal depolarization shift (PDS). In 13-15 DIV neuron-glial cell culture, inhibition of the GABA(A) receptors induces bursts of action potential in the form of clasters PDS and oscillations of intracellular Ca2+ concentration ([Ca2+]i). We demonstrate that GABAergic neurons expressing calcium-permeable AMPA receptors (CP-AMPARs) as well as Kv7-type potassium channels regulate hippocampal glutamatergic neurons' excitability during epileptiform activity in culture. A combination of whole-cell patch-clamp in current clamp mode and calcium imaging microscopy was used to simultaneously register membrane potential and [Ca2+]i level. To identify GABAergic cell cultures were fixed and stained with antibodies against glutamate decarboxylase GAD 65/67 and neuron-specific enolase (NSE) after vital [Ca2+]i imaging. It was shown that CP-AMPARs are involved in the regulation of the PDS clusters and [Ca2+]i pulses accompanied them. Activation of CP-AMPARs of GABAergic neurons is thought to cause the release of GABA, which activates the GABA(B) receptors of other GABAergic interneurons. It is assumed that activation of these GABA(B) receptors leads to the release of beta-gamma subunits of Gi protein, which activate potassium channels, resulting in hyperpolarization and inhibition of these interneurons. The latter causes disinhibition of glutamatergic neurons, the targets of these interneurons. In turn, the CP-AMPAR antagonist, NASPM, has the opposite effect. Measurement of membrane potential in GABAergic neurons by the patch-clamp method in whole-cell configuration demonstrated that NASPM suppresses hyperpolarization in clusters and individual PDSs. It is believed that Kv7-type potassium channels are involved in the control of hyperpolarization during epileptiform activity. The blocker of Kv7 channels, XE 991, mimicked the effect of the CP-AMPARs antagonist on PDS clusters. Both drugs increased the duration of the PDS cluster. In turn, the Kv7 activator, retigabine, decreased the duration of the PDS cluster and Ca2+ pulse. In addition, retigabine led to deep posthyperpolarization at the end of the PDS cluster. The Kv7 channel is believed to be involved in the formation of PDS, as the channel blocker reduced the rate of hyperpolarization in the PDS almost three times. Thus, GABAergic neurons expressing CP-AMPARs, regulate the membrane potential of innervated glutamatergic neurons by modulating the activity of postsynaptic potassium channels of other GABAergic neurons.

Of the Mechanisms of Paroxysmal Depolarization Shifts: Generation and Maintenance of Bicuculline-Induced Paroxysmal Activity in Rat Hippocampal Cell Cultures.

Abnormal depolarization of neuronal membranes called paroxysmal depolarization shift (PDS) represents a cellular correlate of interictal spikes. The mechanisms underlying the generation of PDSs or PDS clusters remain obscure. This study aimed to investigate the role of ionotropic glutamate receptors (iGluRs) in the generation of PDS and dependence of the PDS pattern on neuronal membrane potential. We have shown that significant depolarization or hyperpolarization (by more than ±50 mV) of a single neuron does not change the number of individual PDSs in the cluster, indicating the involvement of an external stimulus in PDS induction. Based on this data, we have suggested reliable protocols for stimulating single PDS or PDS clusters. Furthermore, we have found that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are necessary for PDS generation since AMPAR antagonist NBQX completely suppresses bicuculline-induced paroxysmal activity. In turn, antagonists of NMDA (N-methyl-D-aspartate) and kainate receptors (D-AP5 and UBP310, respectively) caused a decrease in the amplitude of the first action potential in PDSs and in the amplitude of the oscillations of intracellular Ca2+ concentration occurring alongside the PDS cluster generation. The effects of the NMDAR (NMDA receptor) and KAR (kainate receptor) antagonists indicate that these receptors are involved only in the modulation of paroxysmal activity. We have also shown that agonists of some Gi-coupled receptors, such as A1 adenosine (A1Rs) or cannabinoid receptors (CBRs) (N6-cyclohexyladenosine and WIN 55,212-2, respectively), completely suppressed PDS generation, while the A1R agonist even prevented it. We hypothesized that the dynamics of extracellular glutamate concentration govern paroxysmal activity. Fine-tuning of neuronal activity via action on Gi-coupled receptors or iGluRs paves the way for the development of new approaches for epilepsy pharmacotherapy.

Basic Principles of Electroencephalogram

Electroencephalogram(EEG)signals are mainly generated by postsynaptic potentials(EPSP)in the apical dendrites of pyramidal cells in the cortex. The mechanism of generation of interictal epileptiform discharges(IED)is paroxysmal depolarization shift(PDS). IEDs are negative towards the cortical surface and positive towards the white matter. To interpret EEG, readers should know normal EEG waveforms of wakefulness and sleep, normal variants such as wicket spikes or small sharp spikes, and artifacts such as eye movements or electromyography. Overinterpretation of EEG is a major cause of misdiagnosis; therefore, the accurate identification of IED is essential. The International Federation of Clinical Neurophysiology has proposed a criteria for the identification of IED. Long-term video-EEG is useful for correct diagnosis and localization of the epileptogenic zone in the setting of presurgical evaluation of intractable epilepsy and is also useful for the differential diagnosis of epileptic seizures and non-epileptic events. Clinical history and symptomatology are of utmost importance for correct diagnosis. Diagnosis should not be made using only EEG findings.

The Effect of Valproate Sodium on the Electrical Activity of Helix aspersa F1 Neurons in a Pentylenetetrazole-Induced Epileptic Model Using an Intracellular Recording System

Background: Epilepsy is a chronic central nervous system disorder with a high prevalence in modern society. Despite using common anticonvulsant drugs, its control is not adequately achieved. Animal models for seizures play the leading role in advancing our understanding of the cellular mechanisms of epilepsy. The present study was an attempt to elucidate the electrophysiological mechanism of the effect of sodium valproate on the cellular model of epilepsy. Understanding the cellular mechanisms of this drug may help clarify the pharmacological screening of other drugs. Methods: The intracellular recording was made from F1 cells of garden Helix aspersa in the presence of Ringer solution. Following the extracellular application of valproate sodium at a concentration of 10 mM after and before the use of (25mM) epileptogenic agent (pentylenetetrazol (PTZ)), we evaluated its effect on paroxysmal depolarization shift (PDS) and electrophysiological characteristics. Results: These results showed that valproate sodium could reduce neuronal excitability. It could significantly hyperpolarize rest action potential by decreasing the frequency of firing rate and increasing the amplitude of afterhyperpolarization (AHP) and can prevent depolarization of rest action potential by PTZ. Conclusions: The results suggested that valproate sodium could reduce the PTZ-induced hyperexcitation by hyperpolarization of resting membrane potential (RMP), a reduction in AHP amplitude, and firing the frequency.

Role of L-Type Voltage-Gated Calcium Channels in Epileptiform Activity of Neurons.

Epileptic discharges manifest in individual neurons as abnormal membrane potential fluctuations called paroxysmal depolarization shift (PDS). PDSs can combine into clusters that are accompanied by synchronous oscillations of the intracellular Ca2+ concentration ([Ca2+]i) in neurons. Here, we investigate the contribution of L-type voltage-gated calcium channels (VGCC) to epileptiform activity induced in cultured hippocampal neurons by GABA(A)R antagonist, bicuculline. Using KCl-induced depolarization, we determined the optimal effective doses of the blockers. Dihydropyridines (nifedipine and isradipine) at concentrations ≤ 10 μM demonstrate greater selectivity than the blockers from other groups (phenylalkylamines and benzothiazepines). However, high doses of dihydropyridines evoke an irreversible increase in [Ca2+]i in neurons and astrocytes. In turn, verapamil and diltiazem selectively block L-type VGCC in the range of 1–10 μM, whereas high doses of these drugs block other types of VGCC. We show that L-type VGCC blockade decreases the half-width and amplitude of bicuculline-induced [Ca2+]i oscillations. We also observe a decrease in the number of PDSs in a cluster and cluster duration. However, the pattern of individual PDSs and the frequency of the cluster occurrence change insignificantly. Thus, our results demonstrate that L-type VGCC contributes to maintaining the required [Ca2+]i level during oscillations, which appears to determine the number of PDSs in the cluster.

P-EP028. Low-dose perampanel improves refractory cortical myoclonus by the dispersed and suppressed paroxysmal depolarization shifts in the sensorimotor cortex

Introduction. Although low-dose perampanel (PER) is reportedly effective on cortical myoclonus in a limited number of patients, its underlying mechanisms remain unclear. We aimed to extract and elaborate the clinical effects of PER on refractory cortical myoclonus for dose, etiology and also somatosensory-evoked potential (SEP) findings. Method. We examined 18 epilepsy patients with seizure and cortical myoclonus (10 males; mean age, 48.4 ± 16.2 years; Unverricht-Lundborg disease = 7, benign adult familial myoclonus epilepsy = 6, dentatorubral-pallidoluysian atrophy = 2, Gaucher disease = 1, and Lance-Adams syndrome = 2). Based on data accumulated before and after PER treatment, activities of daily life [ADL]), short latency, cortical components of SEP, and PER blood concentration were analyzed. Results. PER (mean dose: 3.2 ± 2.1 mg/day) significantly improved seizure frequency, myoclonus and ADL scores. It also significantly decreased the amplitude of and prolonged correlate with clinical scores among all patients. In contrast, the degree of P25 prolongation ms) significantly correlated with improved ADL score (p = 0.019) and blood PER concentration (p = 0.011). The degree of N33 prolongation (32.1 ± 4.0 to 33.7 ± 3.4 ms) was positively correlated with ADL score and blood PER concentration (p = 0.025 and p = 0.025, respectively). Conclusion. Low-dose PER markedly improved myoclonus and ADL in patients with refractory cortical myoclonus. SEP, especially P25 latency, is a potentially good biomarker to assess the objective effects of PER on intractable cortical myoclonus. ( https://doi.org/10.1016/j.clinph.2019.07.006 ).

On the Origin of Paroxysmal Depolarization Shifts: The Contribution of Cav1.x Channels as the Common Denominator of a Polymorphous Neuronal Discharge Pattern

Since their discovery in the 1960s, the term paroxysmal depolarization shift (PDS) has been applied to a wide variety of reinforced neuronal discharge patterns. Occurrence of PDS as cellular correlates of electrographic spikes during latent phases of insult-induced rodent epilepsy models and their resemblance to giant depolarizing potentials (GDPs) nourished the idea that PDS may be involved in epileptogenesis. Both GDPs and – in analogy – PDS may lead to progressive changes of neuronal properties by generation of pulsatile intracellular Ca2+ elevations. Herein, a key element is the gating of L-type voltage gated Ca2+ channels (LTCCs, Cav1.x family), which may convey Ca2+ signals to the nucleus. Accordingly, the present study investigates various insult-associated neuronal challenges for their propensities to trigger PDS in a LTCC-dependent manner. Our data demonstrate that diverse disturbances of neuronal function are variably suited to induce PDS-like events, and the contribution of LTCCs is essential to evoke PDS in rat hippocampal neurons that closely resemble GDPs. These PDS appear to be initiated in the dendritic sub-compartment. Their morphology critically depends on the position of recording electrodes and on their rate of occurrence. These results provide novel insight into induction mechanisms, origin, variability, and co-existence of PDS with other discharge patterns and thereby pave the way for future investigations regarding the role of PDS in epileptogenesis.

Molecular mechanisms of action determine inhibition of paroxysmal depolarizing shifts by NMDA receptor antagonists in rat cortical neurons

N-methyl-d-aspartate glutamate receptors (NMDARs) are involved in numerous central nervous system (CNS) processes, including epileptiform activity. We used a picrotoxin-induced epileptiform activity model to compare the action of different types of NMDAR antagonists in rat brain slices. Paroxysmal depolarizing shifts (PDS) were evoked by external stimulation in the medial prefrontal cortex (mPFC) slices and recorded in pyramidal cells (PC) and in fast-spiking interneurons (FSI). The NMDAR antagonists APV and memantine reduced the duration of PDS. However, the competitive antagonist APV caused similar effects on the PC and FSI, while the open-channel blocker memantine had a much stronger effect on the PDS in the FSI than in the PC. This difference cannot be explained by a corresponding difference in NMDAR sensitivity to memantine because the drug inhibited the excitatory postsynaptic current (EPSC) similarly in both cell types. Importantly, the PDS were significantly longer in the FSI than in the PC. The degree of PDS inhibition by memantine correlated with individual PDS durations in each cell type. Computer modeling of a synaptic network in the mPFC suggests that the different effects of memantine on the PDS in the PC and FSI can be explained by use dependence of its action. An open-channel blocking mechanism and competition with Mg2+ ions for the binding site result in pronounced inhibition of the long PDS, whereas the short PDS are weakly sensitive. Our results show that peculiarities of kinetics and the mechanism of action largely determine the effects of NMDAR antagonists on physiological and/or pathological processes.

GABA receptor inhibition and severe hypoxia induce a paroxysmal depolarization shift in goldfish neurons.

Mammalian neurons undergo rapid excitotoxic cell death when deprived of oxygen; however, the common goldfish (Carassius auratus) has the unique ability of surviving in oxygen-free waters, under anoxia. This organism utilizes γ-amino butyric acid (GABA) signaling to suppress excitatory glutamatergic activity during anoxic periods. Although GABAA receptor antagonists are not deleterious to the cellular survival, coinhibition of GABAA and GABAB receptors is detrimental by abolishing anoxia-induced neuroprotective mechanisms. Here we show that blocking the anoxic GABAergic neurotransmission induces seizure-like activity (SLA) analogous to a paroxysmal depolarization shift (PDS), with hyperpolarization of action potential (AP) threshold and elevation of threshold currents. The observed PDS was attributed to an increase in excitatory postsynaptic currents (EPSCs) that are normally attenuated with decreasing oxygen levels. Furthermore, for the first time, we show that in addition to PDS, some neurons undergo depolarization block and do not generate AP despite a suprathreshold membrane potential. In conclusion, our results indicate that with severe hypoxia and absence of GABA receptor activity, telencephalic neurons of C. auratus manifest a paroxysmal depolarization shift, a key feature of epileptic discharge.NEW & NOTEWORTHY This work shows that the combination of anoxia and inhibition of GABA receptors induces seizure-like activities in goldfish telencephalic pyramidal and stellate neurons. Importantly, to prevent seizure-like activity, an intact GABA-mediated inhibitory pathway is required.

Reconsidering the neuropathogenic role of paroxysmal depolarization shifts in epilepsy, epileptogenesis and beyond

Reconsidering the neuropathogenic role of paroxysmal depolarization shifts in epilepsy, epileptogenesis and beyond

Low-dose perampanel improves refractory cortical myoclonus by the dispersed and suppressed paroxysmal depolarization shifts in the sensorimotor cortex

ObjectiveTo elucidate the effects of perampanel (PER) on refractory cortical myoclonus for dose, etiology and somatosensory-evoked potential (SEP) findings. MethodsWe examined 18 epilepsy patients with seizure and cortical myoclonus. Based on data accumulated before and after PER treatment, correlations among clinical scores in myoclonus and activities of daily life (ADL); early cortical components of SEP; and PER blood concentration, were analyzed. ResultsPER (mean dose: 3.2 ± 2.1 mg/day) significantly improved seizures, myoclonus and ADL and significantly decreased the amplitude of and prolonged latency of giant SEP components. The degree of P25 and N33 prolongations (23.8 ± 1.6 to 24.7 ± 1.7 ms and 32.1 ± 4.0 to 33.7 ± 3.4 ms) were significantly correlated with improved ADL score (p = 0.019 and p = 0.025) and blood PER concentration (p = 0.011 and p = 0.025), respectively. ConclusionsLow-dose PER markedly improved myoclonus and ADL in patients with refractory cortical myoclonus. Our results suggest that SEP, particularly P25 latency, can be used as a potential biomarker for assessing the objective effects of PER on intractable cortical myoclonus. SignificanceIn this study, PER lessened the degree of synchronized discharges in the postsynaptic neurons in the primary motor cortex.

A Comparative Study of Cell Specific Effects of Systemic and Volatile Anesthetics on Identified Motor Neurons and Interneurons of Lymnaea stagnalis (L.), Both in the Isolated Brain and in Single Cell Culture.

1. A comparative descriptive analysis of systemic (sodium pentobarbital, sodium thiopentone, ketamine) and volatile (halothane, isoflurane, enflurane) general anesthetics revealed important differences in the neuronal responses of identified motor neurons and interneurons in the isolated central nervous system (CNS) and cultured identified neurons in single cell culture of Lymnaea stagnalis (L.).2. At high enough concentrations all anesthetics eventually caused cessation of spontaneous or evoked action potentials, but volatile anesthetics were much faster acting. Halothane at low concentrations caused excitation, thought to be equivalent to the early excitatory phase of anesthesia. Strong synaptic inputs were not always abolished by pentobarbital.3. There were cell specific concentration-dependent responses to halothane and pentobarbital in terms of membrane potential, action potential characteristics, the after hyperpolarization and patterned activity. Individual neurons generated specific responses to the applied anesthetics.4. The inhalation anesthetics, enflurane, and isoflurane, showed little concentration dependence of effect, in contrast to results obtained with halothane. Enflurane was faster acting than halothane and isoflurane was particularly different, producing quiescence in all cells types studied at all concentrations studied.5. Halothane, enflurane, the barbiturate general anesthetics, pentobarbital, and sodium thiopentone and the dissociative anesthetic ketamine, produced two distinctly different effects which could be correlated with cell type and their location in the isolated brain: either a decline in spontaneous and evoked activity prior to quiescence in interneurons or paroxysmal depolarizing shifts (PDS) in motor neurons, again prior to quiescence, which were reversed when the anesthetic was eliminated from the bath. In the strongly electrically coupled motor neurons, VD1 and RPD2, both types of response were observed, depending on the anesthetic used. Thus, with the exception isoflurane, all the motor neurons subjected to the anesthetic agents studied here were capable of generating PDS in situ, but the interneurons did not do so.6. The effects of halothane on isolated cultured neurons indicates that PDS can be generated by single identified neurons in the absence of synaptic inputs. Further, many instances of PDS in neurons that do not generate it in situ have been found in cultured neurons. The nature of PDS is discussed.

The Paroxysmal Depolarization Shift: Reconsidering Its Role in Epilepsy, Epileptogenesis and Beyond.

Paroxysmal depolarization shifts (PDS) have been described by epileptologists for the first time several decades ago, but controversy still exists to date regarding their role in epilepsy. In addition to the initial view of a lack of such a role, seemingly opposing hypotheses on epileptogenic and anti-ictogenic effects of PDS have emerged. Hence, PDS may provide novel targets for epilepsy therapy. Evidence for the roles of PDS has often been obtained from investigations of the multi-unit correlate of PDS, an electrographic spike termed “interictal” because of its occurrence during seizure-free periods of epilepsy patients. Meanwhile, interictal spikes have been found to be associated with neuronal diseases other than epilepsy, e.g., Alzheimer’s disease, which may indicate a broader implication of PDS in neuropathologies. In this article, we give an introduction to PDS and review evidence that links PDS to pro- as well as anti-epileptic mechanisms, and to other types of neuronal dysfunction. The perturbation of neuronal membrane voltage and of intracellular Ca2+ that comes with PDS offers many conceivable pathomechanisms of neuronal dysfunction. Out of these, the operation of L-type voltage-gated calcium channels, which play a major role in coupling excitation to long-lasting neuronal changes, is addressed in detail.

The paroxysmal depolarization shift in epilepsy research.

Several shortcomings with currently available pharmacotherapy of epilepsy necessitate the search for new drug targets. Paroxysmal depolarization shifts (PDS) represent the cellular correlates of electrographic (e.g. interictal) spikes. While the ionic basis of PDS is understood in great detail, controversy exists regarding their proposed implication in epilepsy. To address this issue and to consider potential targetability, this mini-review gives an overview of the ionic conductances contributing to PDS and reflects on the hypotheses of their potential pro-epileptic (epileptogenic) and anti-epileptic roles.

Effects of anti-epileptic drugs on spreading depolarization-induced epileptiform activity in mouse hippocampal slices

Epilepsy and spreading depolarization (SD) are both episodic brain disorders and often exist together in the same individual. In CA1 pyramidal neurons of mouse hippocampal slices, induction of SD evoked epileptiform activities, including the ictal-like bursts, which occurred during the repolarizing phase of SD, and the subsequent generation of paroxysmal depolarization shifts (PDSs), which are characterized by mild depolarization plateau with overriding spikes. The duration of the ictal-like activity was correlated with both the recovery time and the depolarization potential of SD, whereas the parameters of PDSs were not significantly correlated with the parameters of SD. Moreover, we systematically evaluated the effects of multiple anti-epileptic drugs (AEDs) on SD-induced epileptiform activity. Among the drugs that are known to inhibit voltage-gated sodium channels, carbamazepine, phenytoin, valproate, lamotrigine, and zonisamide reduced the frequency of PDSs and the overriding firing bursts in 20–25 min after the induction of SD. The GABA uptake inhibitor tiagabine exhibited moderate effects and partially limited the incidence of PDSs after SD. AEDs including gabapentin, levetiracetam, ethosuximide, felbamate, and vigabatrin, had no significant effect on SD-induced epileptic activity. Taken together, these results demonstrate the effects of AEDs on SD and the related epileptiform activity at the cellular level.

S200 Paroxyzmal depolarization shift – Is it an interictal phenomenon is humans?

Paroxysmal depolarization shift (PDS) was extensively studied in animal models of acute and subacut epilepsy. Based on the observation that PDS occurred between behavioral seizures it had been complemented by interictal discharges, that can be recorded in humans in the seizure onset zone (SOZ) and around. PDS is characterized by excessive discharge of large number of neurons within a certain area of the cortex. Studying human SOZ with microelectrodes revealed that selective or no neuronal firing increase happen during IIDs. In this lecture we demonstrate interictal and ictal neuronal discharge patterns in humans and compare to PDS recordings from animals. Based on similarities and discrepancies we try to conclude how neuronal hyperexcitability can be interpreted in human chronic epilepsy compared to our understanding from animal models.

Modulation of Synaptic Reactions of the “Nociceptive” Neurons in the Cat Cortex upon Stimulation of the Periaqueductal Gray and Application of Some Pharmacological Agents

We examined the effects of electrical stimulation of the periaqueductal gray (PAG) and systemic morphine injections on postsynaptic processes in neurons of the cat somatosensory cortex, which were activated by nociceptive influences. Stimulation of the PAG resulted in long-lasting suppression of synaptic reactions induced by stimulation of dental pulp nociceptors. There was certain parallelism within the conditioning effects of PAG stimulation and effects of systemic introduction of morphine. Ionophoretic application of strychnine on such pyramidal cortical neurons did not evoke paroxysmal depolarization shifts (PDSh) of the membrane potential in such neurons. At the same time, surface application of this agent on the cortex (which influenced extensive populations of cortical neurons) resulted in the development of considerable PDShs. This observation confirms the synaptic nature of the above shifts. Applications of strychnine using both techniques resulted in the blockade of, first of all, early IPSP components in pyramidal neurons but did not affect significantly late components of these potentials; this is indicative of different geneses of the above components. It is supposed that the early IPSP component is generated due to activation of axo-somatic inhibitory synapses, while the late component of such reactions is related to activation of inhibitory synapses localized in the dendrites. The mechanisms of modulation of postsynaptic reactions of somatosensory cortex neurons developing upon activation of high-threshold (nociceptive) afferent inputs are discussed. Such modulation is probably based on changes in both pre- and post-synaptic intracortical cell structures.

Cav 1.3 channels play a crucial role in the formation of paroxysmal depolarization shifts in cultured hippocampal neurons.

An increase of neuronal Cav 1.3 L-type calcium channels (LTCCs) has been observed in various animal models of epilepsy. However, LTCC inhibitors failed in clinical trials of epileptic treatment. There is compelling evidence that paroxysmal depolarization shifts (PDSs) involve Ca2+ influx through LTCCs. PDSs represent a hallmark of epileptiform activity. In recent years, a probable epileptogenic role for PDSs has been proposed. However, the implication of the two neuronal LTCC isoforms, Cav 1.2 and Cav 1.3, in PDSs remained unknown. Moreover, Ca2+ -dependent nonspecific cation (CAN) channels have also been suspected to contribute to PDSs. Nevertheless, direct experimental support of an important role of CAN channel activation in PDS formation is still lacking. Primary neuronal networks derived from dissociated hippocampal neurons were generated from mice expressing a dihydropyridine-insensitive Cav 1.2 mutant (Cav 1.2DHP-/- mice) or from Cav 1.3-/- knockout mice. To investigate the role of Cav 1.2 and Cav 1.3, perforated patch-clamp recordings were made of epileptiform activity, which was elicited using either bicuculline or caffeine. LTCC activity was modulated using the dihydropyridines Bay K 8644 (agonist) and isradipine (antagonist). Distinct PDS could be elicited upon LTCC potentiation in Cav 1.2DHP-/- neurons but not in Cav 1.3-/- neurons. In contrast, when bicuculline led to long-lasting, seizure-like discharge events rather than PDS, these were prolonged in Cav 1.3-/- neurons but not in Cav 1.2DHP-/- neurons. Because only the Cav 1.2 isoform is functionally coupled to CAN channels in primary hippocampal networks, PDS formation does not require CAN channel activity. Our data suggest that the LTCC requirement of PDS relates primarily to Cav 1.3 channels rather than to Cav 1.2 channels and CAN channels in hippocampal neurons. Hence, Cav 1.3 may represent a new therapeutic target for suppression of PDS development. The proposed epileptogenic role of PDSs may allow for a prophylactic rather than the unsuccessful seizure suppressing application of LTCC inhibitors.

The borderland of migraine and epilepsy in children.

To provide a review on the spectrum of migraine-epilepsy disorders in children. The migraine-epilepsy continuum covers a fascinating array of disorders that share many clinical similarities but also differ fundamentally in pathophysiology. In the pediatric population, its study can be complicated by the young age of those affected and the lack of clear understanding of the neurobiology of these disorders within the developing brain. This review serves to discuss the borderland of migraine and epilepsy in children. It will focus on epidemiology and comorbidity of the two disorders, possible mechanisms for shared pathophysiology informed by basic and translational science, and an overview of clinical similarities and differences. It will also discuss differentiation of migraine aura from childhood occipital epilepsies. Finally, the review concludes with a discussion of current classification methods for capturing cases on the migraine-epilepsy spectrum and a call for a united approach towards a better definition of this spectrum of disorders. Recent advances examining the migraine-epilepsy spectrum show clinicopathological similarities between the two disorders in children. Epidemiology demonstrates reciprocally increased incidences of epilepsy in migraineurs and of migraines in children with epilepsy, however, prospective longitudinal in children are currently lacking. Clinically, the two disorders show similarity in preictal, ictal, and postictal phenomena, with close temporal association of the two conditions described by the controversial term of "migralepsy." Basic science research has contributed significant improvements in understanding the generation of both of these episodic neurological conditions, with common links seen at a cellular level involving synaptic glutamate release and the provocation of varying propagation methods including cortical spreading depression in migraine and the paroxysmal depolarizing shift in epilepsy. Despite these significant gains in understanding, improved classification methods are required to identify and further study these interrelated conditions and move towards improved diagnosis and treatment of disorders on the migraine-epilepsy continuum in children.

Rapid chain generation of interpostsynaptic functional LINKs can trigger seizure generation: Evidence for potential interconnections from pathology to behavior.

The experimental finding that a paroxysmal depolarizing shift (PDS), an electrophysiological correlate of seizure activity, is a giant excitatory postsynaptic potential (EPSP) necessitates a mechanism for spatially summating several EPSPs at the level of the postsynaptic terminals (dendritic spines). In this context, we will examine reversible interpostsynaptic functional LINKs (IPLs), a proposed mechanism for inducing first-person virtual internal sensations of higher brain functions concurrent with triggering behavioral motor activity for possible pathological changes that may contribute to seizures. Pathological conditions can trigger a rapid chain generation and propagation of different forms of IPLs leading to seizure generation. A large number of observations made at different levels during both ictal and interictal periods are explained by this mechanism, including the tonic and clonic motor activity, different types of hallucinations, loss of consciousness, gradual worsening of cognitive abilities, a relationship with kindling (which uses an augmented stimulation protocol than that used for inducing long-term potentiation (LTP), which is an electrophysiological correlate of behavioral makers of internal sensation of memory), effect of a ketogenic diet on seizure prevention, dendritic spine loss in seizure disorders, neurodegenerative changes, and associated behavioral changes. The interconnectable nature of these findings is explained as loss of function states of a proposed normal functioning of the nervous system.