Sodium currents in isolated rat CA1 pyramidal and dentate granule neurones in the post-status epilepticus model of epilepsy
Section snippets
Animals and electrode implantation
Eleven adult male Sprague–Dawley rats (Harlan, Zeist, The Netherlands), weighing 385 g at the time of decapitation, were used in this study. The rats were housed in individual cages under a controlled environment (21±1°C; humidity 60%; lights on 08.00–20.00 h). Food and water were available ad libitum. Rats were anaesthetised with an intra-muscular injection of ketamine/xylazine (57/9 mg/kg) and placed in a stereotactic apparatus. For stimulation of the angular bundle, insulated stainless steel
Epileptic state
Long-lasting repetitive stimulation evoked in most rats SE that lasted for 1 h or longer. Rats that did not show SE after stimulation were not incorporated in this study. After stimulation the animals were monitored for up to 3 months. From the second week onward, spontaneous seizures of increasing intensity and severity were recorded. The five chronic epileptic animals incorporated in this study experienced between 4–40 seizures per day of quite variable intensity and duration. All rats had
Discussion
In this study we investigated sodium currents in neurones isolated from the hippocampal CA1 and DG areas of rats that displayed spontaneous seizures 3 months after an electrically induced SE. In the chronic epileptic phase, the sodium conductance per cell was significantly reduced in the CA1 neurones from the SE group, but when expressed as specific sodium conductance this difference vanished, due to a smaller cell size. The kinetics of current activation, inactivation and recovery from
Conclusions
The most prominent difference observed after SE in CA1 was a large window current that had about three times the peak amplitude of controls and was shifted 6 mV to more hyperpolarised potentials. The difference in sodium current could cause spontaneous seizures. It is not clear whether the epileptic activity also directly or indirectly affects the sodium current, thereby creating a feedback loop that maintains the epileptic state. Our observations do not exclude other factors like neurogenesis,
Acknowledgements
These investigations were supported by the National Epilepsy Fund-‘The Power of the Small’, Project Number 98-17.
References (40)
- et al.
Isolation of neurons suitable for patch-clamping from adult mammalian central nervous systems
J. Neurosci. Methods
(1986) - et al.
Altered brain sodium channel transcript levels in human epilepsy
Brain Res. Mol. Brain Res.
(1996) - et al.
Self-sustaining limbic status epilepticus induced by ‘continuous’ hippocampal stimulation: electrographic and behavioral characteristics
Epilepsy Res.
(1989) - et al.
Functional anatomy of hippocampal seizures
Prog. Neurobiol.
(1991) - et al.
In contrast to kindled seizures, the frequency of spontaneous epilepsy in the limbic status model correlates with greater aberrant fascia dentata excitatory and inhibitory axon sprouting, and increased staining for N-methyl-D-aspartate, AMPA and GABA(A) receptors
Neuroscience
(1997) - et al.
Experimental epileptogenesis: kindling-induced epilepsy in rats
Exp. Neurol.
(1978) Modification of seizure activity by electrical stimulation. II. Motor seizure
Electroencephalogr. Clin. Neurophysiol.
(1972)- et al.
Differential up-regulation of voltage-dependent Na+ channels induced by phenytoin in brains of genetically seizure-susceptible (El) and control (ddY) mice
Neuroscience
(1994) - et al.
Sodium currents in isolated rat CA1 neurons after kindling epileptogenesis
Neuroscience
(1998) - et al.
Enhancement of calcium currents in rat hippocampal CA1 neurons induced by kindling epileptogenesis
Neuroscience
(1992)
Potassium currents in isolated CA1 neurons of the rat after kindling epileptogenesis
Neuroscience
Corticosteroid effects on sodium and calcium currents in acutely dissociated rat CA1 hippocampal neurons
Neuroscience
Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy
Eur. J. Neurosci.
A TTX-sensitive inward sodium current contributes to spontaneous activity in newborn rabbit sino-atrial node cells
J. Physiol.
Differential regulation of three sodium channel messenger RNAs in the rat central nervous system during development
EMBO J.
Functional anatomy of spontaneous seizures in a rat model of limbic epilepsy
Epilepsia
Voltage-dependent neuromodulation of Na+ channels by D1-like dopamine receptors in rat hippocampal neurons
J. Neurosci.
Cellular and molecular biology of voltage-gated sodium channels
Physiol. Rev.
Persistent sodium current in mammalian central neurons
Annu. Rev. Physiol.
Mechanisms of action of antiepileptic drugs
Seizure
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2019, Epilepsy ResearchCitation Excerpt :Alterations in the expression of voltage-gated sodium channels such as Nav1.1, Nav1.2 and Nav1.6 predispose neurons towards network hyperexcitability and repetitive firing, and thus may be causally associated with epileptogenesis/ seizure activity (Scharfman, 2002). Various experimental studies have demonstrated changes in biophysical properties of voltage-gated Na+ currents in epilepsy (Ellerkmann et al., 2003; Ketelaars et al., 2001). In addition studies have also shown altered mRNA and protein expression of some α subunits of Na+ channels in the epileptic tissue of human and animals (Klein et al., 2004; Qiao et al., 2013; Xu et al., 2013; Zhu et al., 2016).
Pro-excitatory alterations in sodium channel activity facilitate subiculum neuron hyperexcitability in temporal lobe epilepsy
2017, Neurobiology of DiseaseCitation Excerpt :The current established over this range is commonly referred to as the window current and an enhancement in this range, or “window,” would increase the probability of channel opening, resulting in a reduction in AP thresholds, facilitating AP firing and potentially initiating seizure generation and spread. Increases in window currents have been associated with increased persistent sodium current activity and epileptogenesis in animal models of TLE (Ellerkmann et al., 2003; Ketelaars et al., 2001). In agreement, the voltage range of INaP currents reported in this study is consistent with the voltage range for the estimated window current.
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2014, Journal of Biological ChemistryCitation Excerpt :The reduced phosphorylation in this region in response to acute seizures seen here should enhance Nav current in affected neurons. Increased Nav channel activity, the appearance of a persistent Nav current, and acquired AED insensitivity are seen in neurons obtained from the brains of animal models of epilepsy (25, 27, 37, 38), including KA-induced seizures, and in brain tissue from epilepsy patients (22). Enhancement of ion channel activity is associated with the initial period following seizures and may promote subsequent epileptogenesis (39).
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2012, Handbook of Clinical NeurologyCitation Excerpt :This re-examination of the potential changes in sodium channel expression has come about because of the discovery of multiple isoforms of the voltage-gated sodium channels, the recognition that a number of sodium channel mutations are associated with epilepsy (including some familial forms of TLE associated with HS), and because a number of the effective drugs presumably work on the sodium channel. It has become clear that there is a major shift in the expression of sodium channels in the hippocampus and entorhinal cortex (Aronica et al., 2001; Hargus et al., 2011) with a consequent shift in the voltage-gated sodium channel physiology (Ketelaars et al., 2001; Hargus et al., 2011) and, perhaps just as important, pharmacology (Remy and Beck, 2006; Jones et al., 2009). The shifts in physiology result in sodium channels that have a lower threshold for firing and tend to fire in bursts, thus making the neurons far more likely to have bursts of action potential to less intense stimulation.