Effects of carbonic anhydrase activity on the excitability of hippocampal axons during high-frequency firing.

Epileptic activity is known to cause a lowering of intraneuronal pH, which has been suggested to serve as a feedback signal to terminate seizures. The mechanism of such signaling is unclear, but likely involves an altered function of several types of ligand- and voltage-gated channels in postsynaptic membranes caused by increasing cytosolic and extracellular [H]. In addition, axonal conduction properties may be altered by endogenous pH signals, but this has not been investigated.

Differential role of oxidative stress in synaptic and nonsynaptic in vitro ictogenesis.

It is well established that dysfunctional glucose metabolism and in particular hypoglycemia can lead to hyperexcitability and exacerbate epileptic seizures. The precise mechanisms behind this form of hyperexcitability are still unresolved. The present study investigates to what extent oxidative stress can account for the acute proconvulsant effect of hypoglycemia.

Effect of acute mitochondrial dysfunction on hyperexcitable network activity in rat hippocampus in vitro.

Metabolic stress imposed by epileptic seizures can result in mitochondrial dysfunction, believed to act as positive feedback on epileptogenesis and seizure susceptibility. As the mechanism behind this positive feedback is unclear, the aim of the present study was to investigate the causal link between acute mitochondrial dysfunction and increased seizure susceptibility in hyperexcitable hippocampal networks. Following the induction of spontaneous interictal-like discharges, acute selective pharmacological blockade of either of the mitochondrial respiratory complexes (MRC) I-IV induced seizure-like events (SLE) in 78-100% of experiments.

Role of GABA receptors in proepileptic and antiepileptic effects of an applied electric field in rat hippocampus in vitro.

The mechanisms underlying antiepileptic effects of deep brain stimulation (DBS) are complex and poorly understood. Studies on the effects of applied electric fields on epileptic nervous tissue could enable future advances in DBS treatments. Applied electric fields are known to inhibit or enhance epileptic activity in vitro through direct effects on local neurons, but it is unclear whether trans-synaptic effects participate in such actions.

Opposing effects of 2-deoxy-d-glucose on interictal- and ictal-like activity when K currents and GABA receptors are blocked in rat hippocampus in vitro.

The ketogenic diet (KD), a high-fat, carbohydrate-restricted diet, is used as an alternative treatment for drug-resistant epileptic patients. Evidence suggests that compromised glucose metabolism has a significant role in the anticonvulsant action of the KD; however, it is unclear what part of the glucose metabolism that is important. The present study investigates how selective alterations in glycolysis and oxidative phosphorylation influence epileptiform activity induced by blocking K currents and GABA and NMDA receptors in the hippocampal slice preparation.

Furosemide depresses the presynaptic fiber volley and modifies frequency-dependent axonal excitability in rat hippocampus.

The loop diuretic furosemide is known to have anticonvulsant effects, believed to be exerted through blockade of glial Na-K-2Cl cotransport causing altered volume regulation in brain tissue. The possibility that direct effects of furosemide on neuronal properties could also be involved is supported by previous observations, but such effects have not been thoroughly investigated. In the present study we show that furosemide has two opposing effects on stimulus-induced postsynaptic excitation in the nonepileptic rat hippocampal slice: ) an enhancement of e-s coupling, which depended on intact GABA transmission and was partially mimicked by selective blockade of K-2Cl cotransport, and ) a decrement of field excitatory postsynaptic potentials.

Cognitive deficits caused by a disease-mutation in the α3 Na(+)/K(+)-ATPase isoform.

The Na(+)/K(+)-ATPases maintain Na(+) and K(+) electrochemical gradients across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons. Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na(+)/K(+)-ATPase α3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits. Position D801 in the α3 isoform is a mutational hotspot, with the D801N, D801E and D801V mutations causing AHC and the D801Y mutation causing RDP or mild AHC.

A novel mechanism for the anticonvulsant effect of furosemide in rat hippocampus in vitro.

Though both in vivo and in vitro studies have demonstrated an anticonvulsant effect of the loop diuretic furosemide, the precise mechanism behind this effect is still debated. The current study investigates the effect of furosemide on Cs-induced epileptiform activity (Cs-FP) evoked in area CA1 of rat hippocampal slices in the presence of Cs(+) (5mM) and ionotropic glutamatergic and GABAergic receptor antagonists. As this model diverges in several respects from other epilepsy models it can offer new insight into the mechanism behind the anticonvulsive effect of furosemide.

Intrinsic Ca2+-dependent theta oscillations in apical dendrites of hippocampal CA1 pyramidal cells in vitro.

Behavior-associated theta-frequency oscillation in the hippocampal network involves a patterned activation of place cells in the CA1, which can be accounted for by a somatic-dendritic interference model predicting the existence of an intrinsic dendritic oscillator. Here we describe an intrinsic oscillatory mechanism in apical dendrites of in vitro CA1 pyramidal cells, which is induced by suprathreshold depolarization and consists of rhythmic firing of slow spikes in the theta-frequency band. The incidence of slow spiking (29%) increased to 78% and 100% in the presence of the β-adrenergic agonist isoproterenol (2 μM) or 4-aminopyridine (2 mM), respectively.

Suppression of epileptiform activity by a single short-duration electric field in rat hippocampus in vitro.

The mechanisms behind the therapeutic effects of electrical stimulation of the brain in epilepsy and other disorders are poorly understood. Previous studies in vitro have shown that uniform electric fields can suppress epileptiform activity through a direct polarizing effect on neuronal membranes. Such an effect depends on continuous DC stimulation with unbalanced charge.

Heterogeneous firing behavior during ictal-like epileptiform activity in vitro.

Seizure activity in vivo is caused by populations of neurons displaying a high degree of variability in activity pattern during the attack. The reason for this variability is not well understood. Here we show in an in vitro preparation that hippocampal CA1 pyramidal cells display four types of afterdischarge behavior during stimulus-induced ictal-like events in the presence of Cs(+) (5 mM): type I (43.

Baclofen and adenosine inhibition of synaptic transmission at CA3-CA1 synapses display differential sensitivity to K+ channel blockade.

The metabotropic GABA(B) and adenosine A(1) receptors mediate presynaptic inhibition through regulation of voltage-dependent Ca(2+) channels, whereas K(+) channel regulation is believed to have no role at the CA3-CA1 synapse. We show here that the inhibitory effect of baclofen (20 μM) and adenosine (300 μM) on field EPSPs are differentially sensitive to Cs(+) (3.5 mM) and Ba(2+) (200 μM), but not 4-aminopyridine (100 μM).

Differential influence of non-synaptic mechanisms in two in vitro models of epileptic field bursts.

Non-synaptic interactions are known to promote epileptiform activity through mechanisms that have primarily been studied in one particular in vitro model (low Ca(2+) model). Here we characterize another non-synaptic model, where ictal-like field bursts are induced in the CA1 area of rat hippocampal slices by exposure to Cs(+) (4-5mM) together with blockers of fast chemical synaptic transmission, and compare it with the low Ca(2+) model. The Cs-induced field bursts were blocked by 1 microM tetrodotoxin, but persisted in the presence of 200 microM Cd(2+) or 300 microM Ni(2+).

The slow Ca2+ -dependent K+ -current facilitates synchronization of hyperexcitable pyramidal neurons.

Studies on in vivo and in vitro epilepsy models have shown that progression and maintenance of epileptiform activity can be affected by the slow Ca(2+)-dependent K(+) current (I(sAHP)). This study aimed to investigate the influence of the I(sAHP) on population activity and single cell activity during the transition from the interictal- to the ictal-like phase of an epileptiform field potential induced by Cs(+). Extracellular and intracellular recordings were performed in area CA1 on 400 microm thick hippocampal slices from adult male Wistar rats.

Inwardly rectifying K(+) (Kir) channels antagonize ictal-like epileptiform activity in area CA1 of the rat hippocampus.

Reactive glial cells, for example, from patients with temporal lope epilepsy have a reduced density of inward rectifying K(+) (Kir) channels and thus a reduced K(+) buffering capacity. Evidence is accumulating that this downregulation of Kir channels could be implicated in epileptogenesis. In rat hippocampal brain slices, prolonged exposure to the nonselective Kir channel antagonist, Cs(+) (5 mM), gives rise to an epileptiform field potential (Cs-FP) in area CA1 composed of an initial positive (interictal-like) phase followed by a prolonged negative (ictal-like) phase.

Postnatal development of a new type of epileptiform activity in the rat hippocampus.

Long-term application of Cs(+) (5 mM) induces an epileptiform field potential (Cs-FP) in area CA1 of the rat hippocampus, which is independent of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors and gamma-aminobutyric acid (GABA)(A) receptors. To gain insight into possible mechanisms for the induction of the Cs-FP, we investigated the postnatal development of the response. In brain slices prepared from rats at different ages, the Cs-FP was evoked by stimulation of the Schaffer-collateral-commisural pathway.

New type of synaptically mediated epileptiform activity independent of known glutamate and GABA receptors.

It is well known that excitatory synaptic transmission at the hippocampal CA3-CA1 synapse depends on the binding of released glutamate to ionotropic receptors. Here we report that during long-term application of Cs+ (5 mM), stimulation of the Schaffer collateral-commisural pathway evokes an epileptic field potential (Cs-FP) in area CA1 of the rat hippocampal slice, which is resistant to antagonists of ionotropic glutamate and GABA(A) receptors. The Cs-FP was blocked by N-type but not L-type Ca2+ channel antagonists and was attenuated by adenosine (0.

Influence of the hyperpolarization-activated cation current, I(h), on the electrotonic properties of the distal apical dendrites of hippocampal CA1 pyramidal neurones.

The electrical field application technique has revealed that the electrotonic length of the distal apical dendrites of hippocampal CA1 pyramidal neurones is long compared to the rest of the cell. This difference may be due to an asymmetrical distribution of channels responsible for the leak conductance in distal and proximal membrane segments. One such conductance, the hyperpolarization-activated cation current, I(h), is reported to display an increasing density with distance from the soma along the apical dendrite.