Differential Involvement of L-Type Calcium Channels in Epileptogenesis of Rat Hippocampal Slices during Ontogenesis

Organic calcium channel antagonists block epileptiform activity in adult tissue, suggesting an essential role of L-type channels in epileptogenesis in the mature CNS. By contrast, this remains doubtful for neonatal tissue, as the density of calcium channels changes markedly with ontogenesis. The paper addresses this question by exploring the antiepileptic efficacy of the L-type calcium channel blockers verapamil and nifedipine in low-Mg(2+)-epilepsy in rat hippocampal slices of different postnatal (PN) ages. Field (CA3, CA1) and membrane potentials (CA3) were recorded. Washout of Mg(2+) induced epileptiform potentials, which were blocked age-dependently: Verapamil suppressed activity in all preparations of PN1-5 and PN13-30+, but only in 70% of PN6-12. Nifedipine depressed activity in >75% of slices of PN13-30+, but only in 33% of PN1-12. The findings indicate a role of L-type calcium channels in epileptogenesis from PN13 onwards, with phenylalkylamine-sensitive calcium channels also being involved during PN1-5.

[1]  Z. Bortolotto,et al.  The susceptibility of rats to pilocarpine-induced seizures is age-dependent. , 1987, Brain research.

[2]  R. Köhling,et al.  Contribution of L-type calcium channels to epileptiform activity in hippocampal and neocortical slices of guinea-pigs , 1999, Neuroscience.

[3]  M. Joëls,et al.  Low-threshold calcium current in dendrites of the adult rat hippocampus , 1993, Neuroscience Letters.

[4]  M. Kossut,et al.  Development of NMDA receptor‐channel complex and L‐type calcium channels in mouse hippocampus , 1993, Journal of neuroscience research.

[5]  D. Prince,et al.  Epileptogenesis in immature neocortical slices induced by 4-aminopyridine. , 1995, Brain research. Developmental brain research.

[6]  J. Swann,et al.  The ontogeny of hippocampal local circuits and focal epileptogenesis. , 1992, Epilepsy research. Supplement.

[7]  J. Engel.  Molecular neurobiology of epilepsy , 1992 .

[8]  M. Hines,et al.  Axon terminal hyperexcitability associated with epileptogenesis in vitro. I. Origin of ectopic spikes. , 1993, Journal of neurophysiology.

[9]  D. Johnston,et al.  Subthreshold synaptic activation of voltage-gated Ca2+ channels mediates a localized Ca2+ influx into the dendrites of hippocampal pyramidal neurons. , 1995, Journal of neurophysiology.

[10]  S. D. Meriney,et al.  Developmental Changes in Calcium Current Pharmacology and Somatostatin Inhibition in Chick Parasympathetic Neurons , 1997, The Journal of Neuroscience.

[11]  A. Kriegstein,et al.  Postnatal development of low [Mg2+] oscillations in neocortex. , 1997, Journal of neurophysiology.

[12]  N. Akaike,et al.  Somatostatin modulates high-voltage-activated Ca2+ channels in freshly dissociated rat hippocampal neurons. , 1995, Journal of neurophysiology.

[13]  J. Swann,et al.  Penicillin-induced epileptogenesis in immature rat CA3 hippocampal pyramidal cells. , 1984, Brain research.

[14]  D. Prince,et al.  Patch-clamp studies of voltage-gated currents in identified neurons of the rat cerebral cortex. , 1991, Cerebral cortex.

[15]  M. Spedding,et al.  Classification of calcium channels and the sites of action of drugs modifying channel function. , 1992, Pharmacological reviews.

[16]  H. Matsubayashi,et al.  Ontogenetic development of the specific [3H]nitrendipine binding sites in the rat whole brain. , 1984, Advances in experimental medicine and biology.

[17]  M. Vreugdenhil,et al.  Enhancement of calcium currents in rat hippocampal CA1 neurons induced by kindling epileptogenesis , 1992, Neuroscience.

[18]  S. M. Thompson,et al.  Development of calcium current subtypes in isolated rat hippocampal pyramidal cells. , 1991, The Journal of physiology.

[19]  T. Gloveli,et al.  Properties of low Mg2+ induced epileptiform activity in rat hippocampal and entorhinal cortex slices during adolescence. , 1995, Brain research. Developmental brain research.

[20]  H. Lux,et al.  Activation of three types of membrane currents by various divalent cations in identified molluscan pacemaker neurons , 1989, The Journal of general physiology.

[21]  I. Módy,et al.  Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. , 1987, Journal of neurophysiology.

[22]  A. Dolphin,et al.  Aspects of vertebrate neuronal voltage-activated calcium currents and their regulation , 1991, Progress in Neurobiology.

[23]  J. Walden,et al.  Suppression of recurrent generalized tonic-clonic seizure discharges by intraventricular perfusion of a calcium antagonist. , 1988, Electroencephalography and clinical neurophysiology.

[24]  M. Brodie,et al.  Dihydropyridine Calcium Antagonists in Mice: Blood and Brain Pharmacokinetics and Efficacy Against Pentylenetetrazol Seizures , 1992, Epilepsia.

[25]  P. Schwartzkroin,et al.  Development of rabbit hippocampus: physiology. , 1981, Brain research.

[26]  M. Avoli,et al.  Developmental features of 4-aminopyridine induced epileptogenesis. , 1996, Brain research. Developmental brain research.

[27]  U. Heinemann,et al.  Differential effects of calcium entry blockers on pre- and postsynaptic influx of calcium in the rat hippocampus in vitro , 1987, Brain Research.

[28]  P. Saggau,et al.  Spontaneous interictal-like activity originates in multiple areas of the CA2-CA3 region of hippocampal slices. , 1994, Journal of neurophysiology.

[29]  J N Turner,et al.  Diverse neuronal populations mediate local circuit excitation in area CA3 of developing hippocampus. , 1995, Journal of neurophysiology.

[30]  Y. Ben-Ari,et al.  Giant synaptic potentials in immature rat CA3 hippocampal neurones. , 1989, The Journal of physiology.

[31]  Robert E. Anderson,et al.  Inhibition of electrically induced seizures by a dihydropyridine calcium channel blocker , 1986, Brain Research.

[32]  Cornelius Borck,et al.  On the Structure of Ictal Events in Vitro , 1996, Epilepsia.

[33]  M. Lazdunski,et al.  Autoradiographic analysis in rat brain of the postnatal ontogeny of voltage-dependent Na+ channels, Ca2+-dependent K+ channels and slow Ca2+ channels identified as receptors for tetrodotoxin, apamin and (−)-desmethoxyverapamil , 1987, Brain Research.

[34]  J. Hablitz.  Spontaneous ictal-like discharges and sustained potential shifts in the developing rat neocortex. , 1987, Journal of neurophysiology.

[35]  R C Foehring,et al.  Characterization of pharmacologically identified voltage-gated calcium channel currents in acutely isolated rat neocortical neurons. II. Postnatal development. , 1995, Journal of neurophysiology.

[36]  J R Huguenard,et al.  Low-threshold calcium currents in central nervous system neurons. , 1996, Annual review of physiology.

[37]  O. Witte,et al.  Motor cortical epileptic foci in vivo: actions of a calcium channel blocker on paroxysmal neuronal depolarizations. , 1987, Electroencephalography and clinical neurophysiology.

[38]  R. Foehring,et al.  Characterization of pharmacologically identified voltage-gated calcium channel currents in acutely isolated rat neocortical neurons. I. Adult neurons. , 1995, Journal of neurophysiology.

[39]  P. Carlen,et al.  Patch-clamp study of postnatal development of CA1 neurons in rat hippocampal slices: membrane excitability and K+ currents. , 1992, Journal of neurophysiology.

[40]  N. Akaike,et al.  Comparison of low-threshold Ca2+ currents in the hippocampal CA1 neurons among the newborn, adult and aged rats , 1989, Neuroscience Letters.

[41]  T. Godfraind,et al.  Calcium antagonism and calcium entry blockade. , 1986, Pharmacological reviews.

[42]  J. Gaiarsa,et al.  Postnatal development of pre- and postsynaptic GABAB-mediated inhibitions in the CA3 hippocampal region of the rat. , 1995, Journal of neurophysiology.

[43]  W. Wadman,et al.  Development of HVA and LVA calcium currents in pyramidal CA1 neurons in the hippocampus of the rat. , 1997, Brain research. Developmental brain research.

[44]  E. Speckmann,et al.  Simultaneous blockade of intracellular calcium increases and of neuronal epileptiform depolarizations by verapamil , 1996, Brain Research.

[45]  Edmund M. Talley,et al.  Differential Distribution of Three Members of a Gene Family Encoding Low Voltage-Activated (T-Type) Calcium Channels , 1999, The Journal of Neuroscience.

[46]  U. Heinemann,et al.  Low calcium-induced epileptiform activity in hippocampal slices from infant rats. , 1989, Brain research. Developmental brain research.

[47]  M. Gutnick,et al.  Neuronal activities in epileptogenic foci of immature cortex. , 1972, Transactions of the American Neurological Association.

[48]  A. Gorman,et al.  Internal effects of divalent cations on potassium permeability in molluscan neurones. , 1979, The Journal of physiology.

[49]  J. McIntosh,et al.  Complex patterns of [125I]omega-conotoxin GVIA binding site expression during postnatal rat brain development. , 1994, Brain research. Developmental brain research.

[50]  M. Avoli,et al.  Extracellular potassium elevations in the hippocampus of rats with long-term pilocarpine seizures , 1995, Neuroscience Letters.

[51]  B. Connors,et al.  Intrinsic firing patterns of diverse neocortical neurons , 1990, Trends in Neurosciences.

[52]  R. Köhling,et al.  The effects of verapamil and flunarizine on epileptiform activity induced by bicuculline and low Mg2+ in neocortical tissue of epileptic and primary non-epileptic patients , 1996, Brain Research.

[53]  D. Johnston,et al.  Different Ca2+ channels in soma and dendrites of hippocampal pyramidal neurons mediate spike-induced Ca2+ influx. , 1995, Journal of neurophysiology.