Seizure-like Activities Research Articles

Age-dependent concomitant changes in synaptic dysfunction and GABAergic pathway in the APP/PS1 mouse model.

Synaptic dysfunction is a well-documented manifestation in animal models of Alzheimer's disease pathology. In this context, numerous studies have documented reduction in the functionality of synapses in various models. In addition, recent research has shed more light on increased excitability and its link to seizures and seizure-like activities in AD patients as well as in mouse models. These reports of hyperexcitability contradict the observed reduction in synaptic function and have been suggested to be as a result of the interplay between inhibitory and excitatory neuronal mechanism. The present study therefore investigates functional deficiency in the inhibitory system as complementary to the identified alterations in the glutamate excitatory pathway in AD. Since synaptic function deficit in AD is typically linked to progression/pathology of the disease, it is important to determine whether the deficits in the GABAergic system are functional and can be directly linked to the pattern of the disruption documented in the glutamate system. To build on previous research in this field, experiments were designed to determine if previously documented synaptic dysfunction in AD models is concomitantly observed with excitation/inhibition imbalance as suggested by observation of seizure and seizure-like pathology in such models. We report changes in synaptic function in aged APPPS1 mice not observable in the younger cohort. These changes in synaptic function are furthermore accompanied by alteration in the GABAergic neurotransmission. Thus, age-dependent alteration in the inhibitory/excitatory balance might underpin the symptomatic changes observed with the progression of Alzheimer's disease pathology including sleep disturbance and epileptic events.

Stellate and pyramidal neurons in goldfish telencephalon respond differently to anoxia and GABA receptor inhibition.

With oxygen deprivation, the mammalian brain undergoes hyper-activity and neuronal death while this does not occur in the anoxia-tolerant goldfish (Carassius auratus). Anoxic survival of the goldfish may rely on neuromodulatory mechanisms to suppress neuronal hyper-excitability. As γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, we decided to investigate its potential role in suppressing the electrical activity of goldfish telencephalic neurons. Utilizing whole-cell patch-clamp recording, we recorded the electrical activities of both excitatory (pyramidal) and inhibitory (stellate) neurons. With anoxia, membrane potential (Vm) depolarized in both cell types from -72.2 mV to -57.7 mV and from -64.5 mV to -46.8 mV in pyramidal and stellate neurons, respectively. While pyramidal cells remained mostly quiescent, action potential frequency (APf) of the stellate neurons increased 68-fold. Furthermore, the GABAA receptor reversal potential (E-GABA) was determined using the gramicidin perforated-patch-clamp method and found to be depolarizing in pyramidal (-53.8 mV) and stellate neurons (-42.1 mV). Although GABA was depolarizing, pyramidal neurons remained quiescent as EGABA was below the action potential threshold (-36 mV pyramidal and -38 mV stellate neurons). Inhibition of GABAA receptors with gabazine reversed the anoxia-mediated response. While GABAB receptor inhibition alone did not affect the anoxic response, co-antagonism of GABAA and GABAB receptors (gabazine and CGP-55848) led to the generation of seizure-like activities in both neuron types. We conclude that with anoxia, Vm depolarizes towards EGABA which increases APf in stellate neurons and decreases APf in pyramidal neurons, and that GABA plays an important role in the anoxia tolerance of goldfish brain.

A bio-inspired stimulator to desynchronize epileptic cortical population models: A digital implementation framework

Pathophysiologic neural synchronization is a hallmark of several neurological disorders such as epilepsy. In addition, based on established neurophysiologic findings, astrocytes dynamically regulate the synaptic transmission and have key roles in stabilizing neural synchronization. Therefore, in the present study, based on the dynamic model of astrocyte, a digital bio-inspired stimulator is proposed to avoid the hyper-synchronous seizure-like activities in a cortical population model. The complete digital circuit of the close loop system that is the bio-inspired stimulator and the cortical population model are implemented in hardware on the ZedBoard development kit. Based on the results of MATLAB simulations, hardware synthesis and FPGA implementation, it is demonstrated that the digital bio-inspired stimulator can effectively prevent the occurrence of spontaneous paroxysmal episodes with a demand-controlled characteristic. In this way, the designed digital stimulator successfully maintains the normal ongoing activity.

Treatment with direct-current stimulation against cingulate seizure-like activity induced by 4-aminopyridine and bicuculline in an in vitro mouse model

Clinical studies have shown that cathodal transcranial direct-current stimulation (tDCS) application can produce long-term suppressive effects on drug-resistant seizures. Whether this long-term effect produced by cathodal tDCS can counterbalance the enhancement of synaptic transmission during seizures requires further investigation. Our hypothesis was that the long-term effects of DCS on seizure suppression by the application of cathodal DCS occur through a long-term depression (LTD)-like mechanism. We used a thalamocingulate brain slice preparation combined with a multielectrode array and patch recording to investigate the underlying mechanism of the suppressive effect of DCS on anterior cingulate cortex (ACC) seizures. Patch-clamp recordings showed that cathodal DCS significantly decreased spontaneous excitatory postsynaptic currents (EPSCs) and epileptic EPSCs caused by the 4-aminopyridine. Fifteen minutes of DCS application reliably induced LTD, and the synaptic activation frequency was an important factor in LTD formation. The application of DCS alone without continuous synaptic activation did not induce LTD. Direct-current stimulation-induced LTD appeared to be N-methyl-d-aspartate (NMDA)-dependent, in which the application of the NMDA receptor antagonist D-1-2-amino-5-phosphonopentanoic acid (APV) abolished DCS-induced LTD, and the immediate effect remained. Direct-current stimulation-induced LTD and the long-term effects of DCS on seizure-like activities were also abolished by okadaic acid, a protein phosphatase 1 inhibitor. The long-term effects of DCS on seizures were not influenced by the depotentiation blocker FK-506. Therefore, we conclude that the long-term effects of DCS on seizure-like activities in brain slice occur through an LTD-like mechanism.

Pathological Implications of Oxidative Stress in Patients and Animal Models with Schizophrenia: The Role of Epidermal Growth Factor Receptor Signaling.

Proinflammatory cytokines perturb brain development and neurotransmission and are implicated in various psychiatric diseases, such as schizophrenia and depression. These cytokines often induce the production of reactive oxygen species (ROS) and regulate not only cell survival and proliferation but also inflammatory process and neurotransmission. Under physiological conditions, ROS are moderately produced in mitochondria but are rapidly scavenged by reducing agents in cells. However, brain injury, ischemia, infection, or seizure-like neural activities induce inflammatory cytokines and trigger the production of excessive amounts of ROS, leading to abnormal brain functions and psychiatric symptoms. Protein phosphatases, which are involved in the basal silencing of cytokine receptor activation, are the major targets of ROS. Consistent with this, several ROS scavengers, such as polyphenols and unsaturated fatty acids, attenuate both cytokine signaling and psychiatric abnormalities. In this review, we list the inducers, producers, targets, and scavengers of ROS in the brain and discuss the interaction between ROS and cytokine signaling implicated in schizophrenia and its animal models. In particular, we present an animal model of schizophrenia established by perinatal exposure to epidermal growth factor and illustrate the pathological role of ROS and antipsychotic actions of ROS scavengers, such as emodin and edaravone.

Seizure‐like discharges induced by 4‐aminopyridine in the olfactory system of the in vitro isolated guinea pig brain

The study of the interactions leading to network- or region-specific propagation of seizures is crucial to understand ictogenesis. We have recently found that systemic (arterial) application of the potassium channel blocker, 4-aminopyridine (4AP), induces different and independent seizure activities in olfactory and in limbic structures. Here, we have characterized the network and cellular features that support 4AP-induced seizure-like events in the olfactory cortex. Simultaneous extracellular recordings were performed from the piriform cortex, the entorhinal cortex, the olfactory tubercle, and the amygdala of the in vitro isolated guinea pig brain preparation. Intracellular, sharp electrode recordings were obtained from neurons of different layers of the region of ictal onset, the piriform cortex. Seizure-like discharges were induced by both arterial perfusion and local intracortical injections of 4AP. Arterial application of 4AP induces independent seizure activities in limbic and olfactory cortices. Both local applications of 4AP and cortico-cortical disconnections demonstrated that region-specific seizure-like events initiated in the primary olfactory cortex and propagate to anatomically related areas. Seizures induced by arterial administration of 4-AP are preceded by runs of fast activity at circa 30-40Hz and are independently generated in the hemispheres. Simultaneous extracellular and intracellular recordings in the piriform cortex revealed that the onset of seizure correlates with (1) a gradual amplitude increase of fast activity runs, (2) a large intracellular depolarization with action potential firing of superficial layer neurons, and (3) no firing in a subpopulation of deep layers neurons. During the ictal event, neuronal firing was abolished for 10-30s in all neurons and gradually restored and synchronized before seizure termination. Our data show that olfactory neuronal networks sustain the generation of seizure-like activities that are independent from those observed in adjacent and connected limbic cortex regions. The data support the concept that functionally and anatomically hard-wired networks generate region-specific seizure patterns that could be substrates for system epilepsy.

Multistability in a neuron model with extracellular potassium dynamics

Experiments show a primary role of extracellular potassium concentrations in neuronal hyperexcitability and in the generation of epileptiform bursting and depolarization blocks without synaptic mechanisms. We adopt a physiologically relevant hippocampal CA1 neuron model in a zero-calcium condition to better understand the function of extracellular potassium in neuronal seizurelike activities. The model neuron is surrounded by interstitial space in which potassium ions are able to accumulate. Potassium currents, Na{+}-K{+} pumps, glial buffering, and ion diffusion are regulatory mechanisms of extracellular potassium. We also consider a reduced model with a fixed potassium concentration. The bifurcation structure and spiking frequency of the two models are studied. We show that, besides hyperexcitability and bursting pattern modulation, the potassium dynamics can induce not only bistability but also tristability of different firing patterns. Our results reveal the emergence of the complex behavior of multistability due to the dynamical [K{+}]{o} modulation on neuronal activities.

Spatiotemporal organization and thalamic modulation of seizures in the mouse medial thalamic-anterior cingulate slice

Seizure-like activities generated in anterior cingulate cortex (ACC) are usually classified as simple partial and are associated with changes in autonomic function, motivation, and thought. Previous studies have shown that thalamic inputs can modulate ACC seizure, but the exact mechanisms have not been studied thoroughly. Therefore, we investigated the role of thalamic inputs in modulating ACC seizure-like activities. In addition, seizure onset and propagation are difficult to determine in vivo in ACC. We studied the spatiotemporal changes in epileptiform activity in this cortex in a thalamic-ACC slice to clearly determine seizure onset. We used multielectrode array (MEA) recording and calcium imaging to investigate the modulatory effect of thalamic inputs in a thalamic-ACC slice preparation. Seizure-like activities induced with 4-aminopyridine (4-AP; 250 μm) and bicuculline (5-50 μm) in ACC were attenuated by glutamate receptor antagonists, and the degree of disinhibition varied with the dose of bicuculline. Seizure-like activities were decreased with 1 Hz thalamic stimulation, whereas corpus callosum stimulation could increase ictal discharges. Amplitude and duration of cingulate seizure-like activities were augmented after removing thalamic inputs, and this effect was not observed with those induced with elevated bicuculline (50 μm). Seizure-like activities were initiated in layers II/III and, after thalamic lesions, they occurred mainly in layers V/VI. Two-dimensional current-source density analyses revealed sink signals more frequently in layers V/VI after thalamic lesions, indicating that these layers produce larger excitatory synchronization. Calcium transients were synchronized after thalamic lesions suggesting that ACC seizure-like activities are subjected to desynchronizing modulation by thalamic inputs. Therefore, ACC seizure-like activities are subject to desynchronizing modulation from medial thalamic inputs to deep layer pyramidal neurons. Cingulate seizure-like activities were modulated significantly by thalamic inputs. Repeated stimulation of the thalamus efficiently inhibited epileptiform activity, demonstrating that the desynchronization was pathway-specific. The clinical implications of deep thalamic stimulation in the modulation of cingulate epileptic activity require further investigation.

Age- and region-specific effects of anticonvulsants and bumetanide on 4-aminopyridine-induced seizure-like events in immature rat hippocampal-entorhinal cortex slices

Seizure-like events (SLEs) induced by 4-aminopyridine in rat organotypic slices cultures, which are prepared early after birth, are resistant to standard antiepileptic drugs. In this study we tested the hypothesis that pharmacoresistance may be an intrinsic property of the immature brain. Frequently recurring SLEs presumably representing status epilepticus were induced by 4-aminopyridine in acute rat hippocampal-entorhinal cortex slices obtained from postnatal day 3-19 (P3-P19), and the effects of carbamazepine, phenytoin, valproic acid, and phenobarbital were examined. In addition, bumetanide was tested, which blocks the Na(+) -K(+) -2Cl(-) (NKCC1) cotransporter, and also acetazolamide, which blocks the carbonic anhydrase and thereby the accumulation of bicarbonate inside neurons. The efficacy of all antiepileptic drugs in blocking SLEs was dependent on postnatal age, with low efficacy in P3-P5 slices. Antiepileptic drugs suppressed SLEs more readily in the medial entorhinal cortex (ECm) than in the CA3. In P3-P5 slices, valproic acid and phenobarbital increased both tonic and clonic seizure-like activities in the CA3, whereas phenytoin and carbamazepine blocked tonic-like but prolonged clonic-like activity. In P3-P5 slices, bumetanide often blocked SLEs in the CA3, but was not as effective in the ECm. Like with other antiepileptic drugs, the seizure-suppressing effects of acetazolamide increased with postnatal age. We conclude that pharmacoresistance may be inherent to very immature tissue and suggest that expression of the NKCC1 cotransporter might contribute to pharmacoresistance.

Seizure-Like Activities during Head-Up Tilt Test-Induced Syncope

PurposeSome patients with neurally mediated reflex syncope may be misdiagnosed as epilepsy because myoclonic jerky movements are observed during syncope. The seizure-like activities during the head-up tilt test (HUT) have been rarely reported. The purpose of this study was to assess the characteristics of these seizure-like activities and evaluate whether there are differences in the clinical characteristics and hemodynamic parameters of patients with neurally mediated reflex syncope with and without seizure-like activities during HUT-induced syncope.Materials and MethodsThe medical records of 1,383 consecutive patients with a positive HUT were retrospectively reviewed, and 226 patients were included in this study.ResultsOf 226 patients, 13 (5.75%) showed seizure-like activities, with 5 of these (2.21%) having multifocal myoclonic jerky movements, 5 (2.21%) having focal seizure-like activity involving one extremity, and 3 (1.33%) having upward deviation of eye ball. Comparison of patients with and without seizure-like activities revealed no significant differences in terms of clinical variables and hemodynamic parameters during HUT.ConclusionSeizure-like activities occurred occasionally during HUT-induced syncope in patients with neurally mediated reflex syncope. The seizure-like activities during HUT might not be related to the severity of the syncopal episodes or hemodynamic changes during HUT.

Treatment of Seizures in Newborns: The Dilemma of Starting the Right Drug, at the Right Time, in the Right Doses, and Monitoring the Right Endpoints

A 25-week gestational age newborn, birthweight 650 grams, has several complications in the first 3 days of life including respiratory distress syndrome treated with surfactant, clinical signs of patent ductus arteriosus which is being evaluated to confirm diagnosis and consideration for ligation, and intraventricular hemorrhage diagnosed on the morning of day 3 of life. On the afternoon of day 3, the patient develops seizure-like activities. Symptoms consist of jerking of the right shoulder followed by chewing motions, and are associated with oxygen desaturation and tachycardia. These symptoms occur about 5 times over a one-hour period. An electroencephalogram (EEG) is ordered and three events are noted during a 30 minute recording. A debate about initiating anticonvulsant therapy ensues; the neurologist wants to wait until the EEG is interpreted to initiate an anticonvulsant, while the pharmacotherapy specialist argues for initiating phenobarbital during the EEG, timed to be given during any observed clinical seizure activity or obvious electrographic seizure activity on the EEG. Based on the neurologist’s recommendaTreatment of seizures in Newborns: The Dilemma of starting the Right Drug, at the Right Time, in the Right Doses, and Monitoring the Right endpoints

Cannabinoid suppressed bicuculline-induced convulsion without respiratory depression in the brainstem-spinal cord preparation from newborn rats

Previous studies have suggested that cannabinoid compounds are anticonvulsants and that these compounds depress respiratory activity. However, the anticonvulsant potential of cannabinoids and their depressive effect on respiration have not been evaluated simultaneously. In the present study, we used a brainstem-spinal cord preparation model to investigate changes in inspiratory activity and the anticonvulsant effects of a cannabinoid receptor agonist, WIN 55, 212-2, in bicuculline-induced convulsion. Application of 10 microM WIN 55, 212-2 caused no change in inspiratory activity (6.9+/- 0.89 bursts/min vs. 8.0+/- 1.3 bursts/min, not significant) and decreased bicuculline-induced seizure-like nerve activity (number of seizure-like activities in 10 min, 11+/- 7.4 bursts vs. 1.5+/- 1.6 bursts, P< 0.01; average duration of seizure-like activity, 8.9+/- 4.0 sec vs. 4.7+/- 2.1 sec, P> 0.01). Our results suggest that administration of an appropriate dose of cannabinoid receptor agonist WIN 55,212-2 has an anticonvulsant effect but does not cause respiratory depression.

Substituted hexahydrobenzo[f]thieno[c]quinolines as dopamine D1-selective agonists: synthesis and biological evaluation in vitro and in vivo.

A series of substituted 9,10-dihydroxyhexahydrobenzo[f]thieno[c]quinolines (TB[f]Q), varying with respect to the position of the thiophene relative to the benzo[f]quinoline core and the nature and position of the substituent on the thiophene, were prepared and evaluated for their affinity and selectivity for the dopamine D1-like receptor. The thieno[3,2-c]B[f]Q regioisomers bearing a small alky1 (C1-C3) substituent at the 2 position were potent (Ki < 20 nM) and selective (D2/D1 > 50) D1 agonists with close to full agonist activity (IA > 85%). The compounds were resolved and found to exhibit a high level of enantiospecificity in their interaction with the D1 receptor. Selected compounds were tested in vivo in the 6-OHDA rodent model of Parkinson's disease and for their liability to produce seizure-like activities in mice. (5aR)-trans-2-Propyl-4,5,5a,6,7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol (5) emerged as the compound with the best overall in vivo profile in terms of potency (ED50 = 0.04 mumol/kg) and safety.

5. Seizure-like activity in cell culture

I will describe experiments with neurons in long-term culture that display seizure-like electrical activity. The neurons are dissociated from the hippocampal formation of newborn rats and then chronically exposed to agents that block synaptic transmission, especially glutamatergic transmission. Seizure-like behavior of the neurons develops as the cultures mature and is revealed when the blocking agents are withdrawn. This spontaneous electrical behavior of the culture has many of the characteristics of seizure activity in intact cortex. It can be very intense and can lead to the death of many neurons. This system allows the familiar experimental advantages of dissociated-cell culture to be applied to the study of seizure-like activities. The experiments to be described were all done with mass cultures containing hundreds or thousands of neurons 6. However, many of the seizure-like events observed in mass cultures can also be seen in microcultures containing only a few neurons 25.