Decrease in Synaptic Transmission Can Reverse the Propagation Direction of Epileptiform Activity in Hippocampus In Vivo

2005 ◽  
Vol 93 (3) ◽  
pp. 1158-1164 ◽  
Author(s):  
Zhouyan Feng ◽  
Dominique M. Durand
Keyword(s):  
Synaptic Transmission ◽  
Epileptiform Activity ◽  
Epileptic Activity ◽  
Propagation Direction ◽  
Synaptic Activity ◽  
Multiple Channel ◽  
Ca1 Region ◽  
Partial Suppression

Most types of epileptiform activity with synaptic transmission have been shown to propagate from the CA3 to CA1 region in hippocampus. However, nonsynaptic epileptiform activity induced in vitro is known to propagate slowly from the caudal end of CA1 toward CA2/CA3. Understanding the propagation modes of epileptiform activity, and their causality is important to revealing the underlying mechanisms of epilepsy and developing new treatments. In this paper, the effect of the synaptic transmission suppression on the propagation of epilepsy in vivo was investigated by using multiple-channel recording probes in CA1. Nonsynaptic epileptiform activity was induced by calcium chelator EGTA with varied concentrations of potassium. For comparison, disinhibition synaptic epileptiform activity was induced by picrotoxin (PTX) with or without partial suppression of excitatory synaptic transmission. The propagation velocity was calculated by measuring the time delay between two electrodes separated by a known distance. The results show that in vivo nonsynaptic epileptiform activity propagates with a direction and velocity comparable to those observed in in vitro preparations. The direction of propagation for nonsynaptic activity is reversed from the PTX-induced synaptic activity. A reversal in propagation direction and change in velocity were also observed dynamically during the process of synaptic transmission suppression. Even a partial suppression of synaptic transmission was sufficient to significantly change the propagation direction and velocity of epileptiform activity. These results suggest the possibility that the measurement of propagation can provide important information about the synaptic mechanism underlying epileptic activity.

Low-Calcium Epileptiform Activity in the Hippocampus In Vivo

2003 ◽  
Vol 90 (4) ◽  
pp. 2253-2260 ◽  
Author(s):  
Zhouyan Feng ◽  
Dominique M. Durand
Keyword(s):  
Synaptic Transmission ◽  
Epileptiform Activity ◽  
Brain Slices ◽  
Early Period ◽  
Epileptic Activity ◽  
Slow Waves ◽  
Stratum Radiatum ◽  
Low Calcium

It has been clearly established that nonsynaptic interactions are sufficient for generating epileptiform activity in brain slices. However, it is not known whether this type of epilepsy model can be generated in vivo. In this paper we investigate low-calcium nonsynaptic epileptiform activity in an intact hippocampus. The calcium chelator EGTA was used to lower [Ca2+]o in the hippocampus of urethane anesthetized rats. Spontaneous and evoked field potentials in CA1 pyramidal stratum and in CA1 stratum radiatum were recorded using four-channel silicon recording probes. Three different types of epileptic activity were observed while synaptic transmission was gradually blocked by a decline in hippocampal [Ca2+]o. A short latency burst, named early-burst, occurred during the early period of EGTA application. Periodic slow-waves and a long latency high-frequency burst, named late-burst, were seen after synaptic transmission was mostly blocked. Therefore these activities appear to be associated with nonsynaptic mechanisms. Moreover, the slow-waves were similar in appearance to the depolarization potential shifts in vitro with low calcium. In addition, excitatory postsynaptic amino acid antagonists could not eliminate the development of slow-waves and late-bursts. The slow-waves and late-bursts were morphologically similar to electrographic seizure activity seen in patients with temporal lobe epilepsy. These results clearly show that epileptic activity can be generated in vivo in the absence of synaptic transmission. This type of low-calcium nonsynaptic epilepsy model in an intact hippocampus could play an important role in revealing additional mechanisms of epilepsy disorders and in developing novel anti-convulsant drugs.

scholarly journals Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury

2018 ◽  
Author(s):  
Jenny B. Koenig ◽  
David Cantu ◽  
Cho Low ◽  
Farzad Noubary ◽  
Danielle Croker ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Epileptiform Activity ◽  
Synaptic Activity ◽  
Network Function ◽  
Cortical Hyperexcitability ◽  
Glycolytic Inhibitor ◽  
Cortical Slices

AbstractTraumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approach based on the ketogenic diet, a neuroprotective and anticonvulsant dietary therapy which results in reduced glycolysis and increased ketosis. Utilizing a pharmacologic inhibitor of glycolysis (2-deoxyglucose, or 2-DG), we found that acute in vitro glycolytic inhibition decreased the excitability of excitatory neurons, but not inhibitory interneurons, in cortical slices from naïve mice. Employing the controlled cortical impact (CCI) model of TBI in mice, we found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in acute cortical slices 3-5 weeks after TBI. One week of in vivo 2-DG treatment immediately after TBI prevented the development of epileptiform activity, restored excitatory and inhibitory synaptic activity, and attenuated loss of parvalbumin-positive inhibitory interneurons. In summary, inhibition of glycolysis with 2-DG may have therapeutic potential to restore network function following TBI.One Sentence SummaryFollowing traumatic brain injury in mice, in vivo treatment with the glycolytic inhibitor 2-deoxyglucose prevented cortical network pathology including cortical hyperexcitability, changes in synaptic activity, and loss of parvalbumin-expressing GABAergic interneurons.

Extracellular pH Responses in CA1 and the Dentate Gyrus During Electrical Stimulation, Seizure Discharges, and Spreading Depression

2000 ◽  
Vol 83 (6) ◽  
pp. 3519-3524 ◽  
Author(s):  
Zhi-Qi Xiong ◽  
Janet L. Stringer
Keyword(s):  
Dentate Gyrus ◽  
Spreading Depression ◽  
Seizure Activity ◽  
Epileptiform Activity ◽  
Extracellular Ph ◽  
Extracellular Acidification ◽  
Ca1 Region ◽  
Activity Dependent

Since neuronal excitability is sensitive to changes in extracellular pH and there is regional diversity in the changes in extracellular pH during neuronal activity, we examined the activity-dependent extracellular pH changes in the CA1 region and the dentate gyrus. In vivo, in the CA1 region, recurrent epileptiform activity induced by stimulus trains, bicuculline, and kainic acid resulted in biphasic pH shifts, consisting of an initial extracellular alkalinization followed by a slower acidification. In vitro, stimulus trains also evoked biphasic pH shifts in the CA1 region. However, in CA1, seizure activity in vitro induced in the absence of synaptic transmission, by perfusing with 0 Ca2+/5 mM K+medium, was only associated with extracellular acidification. In the dentate gyrus in vivo, seizure activity induced by stimulation to the angular bundle or by injection of either bicuculline or kainic acid was only associated with extracellular acidification. In vitro, stimulus trains evoked only acidification. In the dentate gyrus in vitro, recurrent epileptiform activity induced in the absence of synaptic transmission by perfusion with 0 Ca2+/8 mM K+medium was associated with extracellular acidification. To test whether glial cell depolarization plays a role in the regulation of the extracellular pH, slices were perfused with 1 mM barium. Barium increased the amplitude of the initial alkalinization in CA1 and caused the appearance of alkalinization in the dentate gyrus. In both CA1 and the dentate gyrus in vitro, spreading depression was associated with biphasic pH shifts. These results demonstrate that activity-dependent extracellular pH shifts differ between CA1 and dentate gyrus both in vivo and in vitro. The differences in pH fluctuations with neuronal activity might be a marker for the basis of the regional differences in seizure susceptibility between CA1 and the dentate gyrus.

Somatostatin Acts in CA1 and CA3 to Reduce Hippocampal Epileptiform Activity

1999 ◽  
Vol 81 (4) ◽  
pp. 1626-1635 ◽  
Author(s):  
Melanie K. Tallent ◽  
George R. Siggins
Keyword(s):  
Mossy Fiber ◽  
Epileptiform Activity ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Limbic Seizures ◽  
Ca1 Region ◽  
C Fibers ◽  
Ca3 Neurons

Somatostatin acts in CA1 and CA3 to reduce hippocampal epileptiform activity. Although the peptide somatostatin (SST) has been speculated to function in temporal lobe epilepsy, its exact role is unclear, as in vivo studies have suggested both pro- and anticonvulsant properties. We have shown previously that SST has multiple inhibitory cellular actions in the CA1 region of the hippocampus, suggesting that in this region SST should have antiepileptic actions. To directly assess the effect of SST on epileptiform activity, we studied two in vitro models of epilepsy in the rat hippocampal slice preparation using extracellular and intracellular recording techniques. In one, GABA-mediated neurotransmission was inhibited by superfusion of the GABAA receptor antagonist bicuculline. In the second, we superfused Mg2+-free artificial cerebrospinal fluid to remove the Mg2+ block of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor. We show here that SST markedly reduces the intensity of evoked epileptiform afterdischarges and the frequency of spontaneous bursts in both CA1 and CA3. SST appears to act additively in the two regions to suppress the transmission of epileptiform events through the hippocampus. We further examined SST’s actions in CA3 and found that SST dramatically reduced the frequency of paroxysmal depolarizing shifts (PDSs) recorded intracellularly in current clamp, as well as increasing the threshold for evoking “giant” excitatory postsynaptic currents (EPSCs), large polysynaptically mediated EPSCs that are the voltage-clamp correlate of PDSs. We also examined the actions of SST on pharmacologically isolated EPSCs generated at both mossy fiber (MF) and associational/commissural (A/C) synapses. SST appears to act specifically to reduce recurrent excitation between CA3 neurons because it depresses A/C- but not MF-evoked EPSCs. SST also increased paired-pulse facilitation of A/C EPSCs, suggesting a presynaptic site of action. Reciprocal activation of CA3 neurons through A/C fibers is critical for generation of epileptiform activity in hippocampus. Thus SST reduces feedforward excitation in rat hippocampus, acting to “brake” hyperexcitation. This is a function unique from that described for other hippocampal neuropeptides, which affect more standard neurotransmission. Our results suggest that SST receptors could be a unique, selective clinical target for treatment of limbic seizures.

scholarly journals The Effect of Anti-seizure Medications on the Propagation of Epileptic Activity: A Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Mohamed Khateb ◽  
Noam Bosak ◽  
Moshe Herskovitz
Keyword(s):  
Epileptiform Activity ◽  
Clinical Importance ◽  
Brain Structures ◽  
Epileptic Activity ◽  
Point Of View ◽  
Interesting Phenomenon ◽  
Poor Neurological Outcome ◽  
Seizure Propagation

The propagation of epileptiform events is a highly interesting phenomenon from the pathophysiological point of view, as it involves several mechanisms of recruitment of neural networks. Extensive in vivo and in vitro research has been performed, suggesting that multiple networks as well as cellular candidate mechanisms govern this process, including the co-existence of wave propagation, coupled oscillator dynamics, and more. The clinical importance of seizure propagation stems mainly from the fact that the epileptic manifestations cannot be attributed solely to the activity in the seizure focus itself, but rather to the propagation of epileptic activity to other brain structures. Propagation, especially when causing secondary generalizations, poses a risk to patients due to recurrent falls, traumatic injuries, and poor neurological outcome. Anti-seizure medications (ASMs) affect propagation in diverse ways and with different potencies. Importantly, for drug-resistant patients, targeting seizure propagation may improve the quality of life even without a major reduction in simple focal events. Motivated by the extensive impact of this phenomenon, we sought to review the literature regarding the propagation of epileptic activity and specifically the effect of commonly used ASMs on it. Based on this body of knowledge, we propose a novel classification of ASMs into three main categories: major, minor, and intermediate efficacy in reducing the propagation of epileptiform activity.

scholarly journals Epileptiform Discharges With In-Vivo-Like Features in Slices of Rat Piriform Cortex With Longitudinal Association Fibers

2001 ◽  
Vol 86 (5) ◽  
pp. 2445-2460 ◽  
Author(s):  
Rezan Demir ◽  
Lewis B. Haberly ◽  
Meyer B. Jackson
Keyword(s):  
Seizure Activity ◽  
Epileptiform Activity ◽  
Piriform Cortex ◽  
Brain Slices ◽  
Epileptiform Discharges ◽  
Local Circuitry ◽  
Association Fibers ◽  
Discharge Propagation

Brain slices serve as useful models for the investigation of epilepsy. However, the preparation of brain slices disrupts circuitry and severs axons, thus complicating efforts to relate epileptiform activity in vitro to seizure activity in vivo. This issue is relevant to studies in transverse slices of the piriform cortex (PC), the preparation of which disrupts extensive rostrocaudal fiber systems. In these slices, epileptiform discharges propagate slowly and in a wavelike manner, whereas such discharges in vivo propagate more rapidly and jump abruptly between layers. The objective of the present study was to identify fiber systems responsible for these differences. PC slices were prepared by cutting along three different nearly orthogonal planes (transverse, parasagittal, and longitudinal), and epileptiform discharges were imaged with a voltage-sensitive fluorescent dye. Interictal-like epileptiform activity was enabled by either a kindling-like induction process or disinhibition with bicuculline. The pattern of discharge onset was very similar in slices cut in different planes. As described previously in transverse PC slices, discharges were initiated in the endopiriform nucleus (En) and adjoining regions in a two-stage process, starting with low-amplitude “plateau activity” at one site and leading to an accelerating depolarization and discharge onset at another nearby site. The similar pattern of onset in slices of various orientations indicates that the local circuitry and neuronal properties in and around the En, rather than long-range fibers, assume dominant roles in the initiation of epileptiform activity. Subtle variations in the onset site indicate that interneurons can fine tune the site of discharge onset. In contrast to the mode of onset, discharge propagation showed striking variations. In longitudinal slices, where rostrocaudal association fibers are best preserved, discharge propagation resembled in vivo seizure activity in the following respects: propagation was as rapid as in vivo and about two to three times faster than in other slices; discharges jumped abruptly between the En and PC; and discharges had large amplitudes in superficial layers of the PC. Cuts in longitudinal slices that partially separated the PC from the En eliminated these unique features. These results help clarify why epileptiform activity differs between in vitro and in vivo experiments and suggest that rostrocaudal pyramidal cell association fibers play a major role in the propagation of discharges in the intact brain. The longitudinal PC slice, which best preserves these fibers, is ideally suited for the study their role.

Conditions Sufficient for Nonsynaptic Epileptogenesis in the CA1 Region of Hippocampal Slices

2002 ◽  
Vol 87 (1) ◽  
pp. 62-71 ◽  
Author(s):  
Marom Bikson ◽  
Scott C. Baraban ◽  
Dominique M. Durand
Keyword(s):  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Seizure Threshold ◽  
Ion Selective Electrodes ◽  
Receptor Antagonists ◽  
Sodium Conductance ◽  
Ca1 Region ◽  
Persistent Sodium Conductance

Nonsynaptic mechanisms exert a powerful influence on seizure threshold. It is well-established that nonsynaptic epileptiform activity can be induced in hippocampal slices by reducing extracellular Ca2+ concentration. We show here that nonsynaptic epileptiform activity can be readily induced in vitro in normal (2 mM) Ca2+ levels. Those conditions sufficient for nonsynaptic epileptogenesis in the CA1 region were determined by pharmacologically mimicking the effects of Ca2+ reduction in normal Ca2+ levels. Increasing neuronal excitability, by removing extracellular Mg2+ and increasing extracellular K+ (6–15 mM), induced epileptiform activity that was suppressed by postsynaptic receptor antagonists [d-(−)-2-amino-5-phosphonopentanoic acid, picrotoxin, and 6,7-dinitroquinoxaline-2,3-dione] and was therefore synaptic in nature. Similarly, epileptiform activity induced when neuronal excitability was increased in the presence of KCaantagonists (verruculogen, charybdotoxin, norepinephrine, tetraethylammonium salt, and Ba2+) was found to be synaptic in nature. Decreases in osmolarity also failed to induce nonsynaptic epileptiform activity in the CA1 region. However, increasing neuronal excitability (by removing extracellular Mg2+ and increasing extracellular K+) in the presence of Cd2+, a nonselective Ca2+channel antagonist, or veratridine, a persistent sodium conductance enhancer, induced spontaneous nonsynaptic epileptiform activity in vitro. Both novel models were characterized using intracellular and ion-selective electrodes. The results of this study suggest that reducing extracellular Ca2+ facilitates bursting by increasing neuronal excitability and inhibiting Ca2+ influx, which might, in turn, enhance a persistent sodium conductance. Furthermore, these data show that nonsynaptic mechanisms can contribute to epileptiform activity in normal Ca2+ levels.

NO inhibits supraoptic oxytocin and vasopressin neurons via activation of GABAergic synaptic inputs

2001 ◽  
Vol 280 (6) ◽  
pp. R1815-R1822 ◽  
Author(s):  
Javier E. Stern ◽  
Mike Ludwig
Keyword(s):  
Neuronal Excitability ◽  
Cell Types ◽  
Synaptic Activity ◽  
No Donor ◽  
Whole Cell Patch Clamp ◽  
Electrophysiological Recordings ◽  
Neuronal Types ◽  
Vasopressin Neurons

To study modulatory actions of nitric oxide (NO) on GABAergic synaptic activity in hypothalamic magnocellular neurons in the supraoptic nucleus (SON), in vitro and in vivo electrophysiological recordings were obtained from identified oxytocin and vasopressin neurons. Whole cell patch-clamp recordings were obtained in vitro from immunochemically identified oxytocin and vasopressin neurons. GABAergic synaptic activity was assessed in vitro by measuring GABAA miniature inhibitory postsynaptic currents (mIPSCs). The NO donor and precursor sodium nitroprusside (SNP) and l-arginine, respectively, increased the frequency and amplitude of GABAA mIPSCs in both cell types ( P ≤ 0.001). Retrodialysis of SNP (50 mM) onto the SON in vivo inhibited the activity of both neuronal types ( P ≤ 0.002), an effect that was reduced by retrodialysis of the GABAA-receptor antagonist bicuculline (2 mM, P≤ 0.001). Neurons activated by intravenous infusion of 2 M NaCl were still strongly inhibited by SNP. These results suggest that NO inhibition of neuronal excitability in oxytocin and vasopressin neurons involves pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON.

scholarly journals Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1578 ◽  
Author(s):  
Laura Walrave ◽  
Mathieu Vinken ◽  
Luc Leybaert ◽  
Ilse Smolders
Keyword(s):  
Transmembrane Protein ◽  
Epileptiform Activity ◽  
Brain Slices ◽  
High Energy ◽  
Experimental Models ◽  
Functional Coupling ◽  
Seizure Outcome ◽  
Mrna Levels

In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K+ and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca2+ waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments.

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