Possible mechanisms underlying hyperexcitability in the epileptic mutant mouse tottering

  • G. K. Kostopoulos
  • C. T. Psarropoulou
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 35)


Tottering mice present a useful experimental model of genetically determined generalized epilepsy of the absence type. In electrophysiological recordings from hippocampal slices in vitro we found that the postsynaptic excitability (firing threshold) of pyramidal neurons in the CA1 area of tg/tg slices was significantly higher than that of normal slices. In spite of this hyperexcitability, in vitro epileptiform discharges were not observed spontaneously, or upon provocation by intracellular depolarizing pulses, or in response to moderate elevations (+2 mM) in extracellular potassium. The latter elevations actually induced significantly smaller increases in the CA1 synaptic responses of tg/tg as compared to normal slices. The hyperexcitability of tottering neurons could not be explained in terms of altered membrane electrical properties or any reduction of synaptic inhibition or increased capacity for long-term potentiation. Responses to noradrenaline, histamine and adenosine, as well as to the release of N-methyl-D-asparate channels — by eliminating Mg2+ — were comparable in tg/tg and normal slices. These studies show that hyperexcitability can be co-inherited with epilepsy and in this model its expression can be maintained in vitro. The neuronal mechanism of this expression remains elusive, as it does not appear to include some features known to be shared by experimental models of chemically or electrically induced epilepsy.


Hippocampal Slice Epileptiform Discharge Generalize Epilepsy Stratum Radiatum Extracellular Potassium 


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  1. Angelatou F, Pagonopoulou O, Kostopoulos G (1990) Alterations of Al adenosine receptors in different mouse brain areas after pentylentetrazol-induced seizures but not in the epileptic mutant mouse tottering. Brain Res 534: 251–256PubMedCrossRefGoogle Scholar
  2. Avoli M, Gloor P, Kostopoulos G, Naquet R (eds) (1990) Generalized epilepsy: neurobiological approaches. Birkhäuser, BostonGoogle Scholar
  3. Avoli M, Hwa GGC, Drapeau G, Kostopoulos G, Perreault P, Olivier A, Villemeure J-G (1992) Electrophysiological analysis of human neocortex in vitro: experimental techniques and methodological approaches. Can J Neurol Sci (in press)Google Scholar
  4. Ben-Ari Y, Krnjevic K, Reinhardt W (1979) Hippocampal seizures and failure of inhibition. Can J Physiol Pharmacol 57: 1462–1466CrossRefGoogle Scholar
  5. Bliss TVP (1990) Maintainance is presynaptic. Nature 346: 698–699PubMedCrossRefGoogle Scholar
  6. Bliss TVP, Lynch MA (1988) Long-term potentiation of synaptic transmission in the hippocampus: properties and mechanisms. In: Landfield PW, Deadwyller PW (eds) Long-term potentiation: from biophysics to behavior. Alan R Liss, New York, pp 3–72Google Scholar
  7. Buzsaki G (1984) Feed-forward inhibition in the hippocampal formation. Prog Neurobiol 22: 131–153PubMedCrossRefGoogle Scholar
  8. Cain DP (1989) Long-term potentiation and kindling: how similar are the mechanisms? TINS 12 (1): 6–10PubMedGoogle Scholar
  9. Collingridge GL, Bliss TVP (1987) NMDA receptors — their role in long-term potentiation. Trends Neurosci 10: 288–293CrossRefGoogle Scholar
  10. Dingledine R, Gjerstad L (1980) Reduced inhibition during epileptiform activity in the in vitro hippocampal slice. J Physiol (Lond) 305: 297–313Google Scholar
  11. Dingledine R, Hynes MA, King GL (1986) Involvement of N-methyl-D-aspartate receptors in epileptiform bursting in the rat hippocampal slice. J Physiol (Lond) 380: 175–189Google Scholar
  12. Dragunow M (1988) Purinergic mechanisms in epilepsy. Prog Neurobiol 31: 85–108 Ganetsky B, Wu C-F (1985) Genes and membrane excitability in Drosophila. Trends Neurosci 8: 322–326Google Scholar
  13. Gloor P, Fariello RG (1988) Generalized epilepsy: some of its cellular mechanisms differ from those of focal epilepsy. Trends Neurosci 11 (2): 63–68PubMedCrossRefGoogle Scholar
  14. Gloor P, Metrakos J, Metrakos K, Andermann E, van Gelder N (1982) Neurophysiological, genetic and biochemical nature of the epileptic diathesis. Electroencephalogr Clin Neurophysiol [Suppl 35]: 45–56Google Scholar
  15. Gloor P, Avoli M, Kostopoulos G (1990) Thalamocortical relationships in generalized epilepsy with bilaterally synchronous spike-and-wave discharge. In: Avoli M, Gloor P, Kostopoulos G, Naquet R (eds) Generalized epilepsy: neurobiological approaches. Birkhäuser, Boston, pp 190–212Google Scholar
  16. Haas HL, Rose G (1984) The role of inhibitory mechanisms in hippocampal long-term potentiation. Neurosci Lett 47: 301–306PubMedCrossRefGoogle Scholar
  17. Hemmendinger LM, Moore RY (1983) Synaptic reorganization in rat motor trigeminal nucleus following neonatal 6-hydroxy-dopamine treatment. Soc Neurosci Abstr 9: 988Google Scholar
  18. Hopkins WF, Johnston D (1988) Noradrenergic enhancement of long-term potentiation at mossy fiber synapses in the hippocampus. J Neurophysiol 59 (2): 667–687PubMedGoogle Scholar
  19. Jackson JH (1931) Selected writings of John Hughlings Jackson, vol 1. On epilepsy and epileptiform convulsions (edited by Taylor J). Hodder and Stroughton, London, p 500Google Scholar
  20. Jasper HH, van Gelder NM (eds) (1983) Basic mechanisms of neuronal hyperexcitability. Alan R Liss, New York, pp 495Google Scholar
  21. Jonzon B, Fredholm BB (1984) Adenosine receptor mediated inhibition of nor- adrenaline release from slices of the rat hippocampus. Life Sci 35: 1971–1979PubMedCrossRefGoogle Scholar
  22. Kahn SU, Wilson CL, Isokawa-Akesson M, Babb TL, Levesque MF (1989) Increased paired-pulse inhibition in the epileptogenic human temporal lobe. Soc Neurosci Abstr 15 (1): 236Google Scholar
  23. Kaplan BJ, Seyfred TN, Glaser GH (1979) Spontaneous polyspike discharges in an epileptic mutant mouse (tottering). Exp Neurol 66: 577–586PubMedCrossRefGoogle Scholar
  24. Kapur J, Lothman EW (1989) Loss of inhibition precedes delayed spontaneous seizures in the hippocampus after tetanic electrical stimulation. J Neurophysiol 61 (2): 427–434PubMedGoogle Scholar
  25. King GL, Dingledine R, Giachinno JL, McNamara JO (1985) Abnormal neuronal excitability in hippocampal slices from kindled rats. J Neurophysiol 54(5): 1295–1304PubMedGoogle Scholar
  26. Kostopoulos G (1988) Adenosine: a molecule for synaptic homeostasis? In: Avoli M, Reader TA, Dykes RW, Gloor P (eds) Neurotransmitters and cortical function. Plenum Press, New York, pp 415–435CrossRefGoogle Scholar
  27. Kostopoulos G (1992) The tottering mouse: a critical review of its usefulness in the study of the neuronal mechanisms underlying epilepsy (this volume)Google Scholar
  28. Kostopoulos G, Psarropoulou C (1990) Increased postsynaptic excitability in hippo- campal slices from the tottering epileptic mutant mouse. Epilepsy Res 6: 49–55PubMedCrossRefGoogle Scholar
  29. Kostopoulos G, Gloor P, Pellegrini A, Gotman J (1981) A study of the transition from spindles to spike and wave discharge in feline generalized penicillin epilepsy: microphysiological features. Exp Neurol 73: 55–77PubMedCrossRefGoogle Scholar
  30. Kostopoulos G, Avoli M, Gloor P (1983) Participation of cortical recurrent inhibition in the genesis of spike and wave discharges in feline generalized penicillin epilepsy. Brain Res 227: 101–112CrossRefGoogle Scholar
  31. Kostopoulos G, Veronikis DK, Efthimiou I (1987) Caffeine blocks absence seizures in the tottering mutant mouse. Epilepsia 28 (4): 415–420PubMedCrossRefGoogle Scholar
  32. Kostopoulos G, Psarropoulou C, Haas H (1988) Membrane properties, response to amines and to tetanic stimulation of hippocampal neurons in the genetically epileptic mutant mouse tottering. Exp Brain Res 72: 45–50PubMedCrossRefGoogle Scholar
  33. Krnjevic K (1983) GABA — mediated inhibitory mechanisms in relation to epileptic discharges. In: Jasper HH, Van Gelder NM (eds) Basic mechanisms of neuronal hyperexcitability. Alan R Liss, New York, pp 249–280Google Scholar
  34. Levitt P, Noebels JL (1981) Mutant mouse tottering: selective increase of locus coeruleus axons in a defined single-locus mutation. Proc Natl Acad Sci U.S.A. 78: 4630–4634PubMedCrossRefGoogle Scholar
  35. Levitt P, Law C, Pylypiw A, Ross LL (1984) Central adrenergic receptors in the inherited noradrenergic hyperinnervated mutant mouse tottering. Neurosci Abstr 10: 179Google Scholar
  36. Lopes da Silva FH (1987) Hippocampal kindling: physiological evidence for progressive inhibition. Adv Epileptol 16: 57–62Google Scholar
  37. Madison DV, Nicoll RA (1988) Noradrenaline decreases synaptic inhibition in the rat hippocampus. Brain Res 442: 131–138PubMedCrossRefGoogle Scholar
  38. Malouf AT, Robbins CA, Schwartzkroin PA (1990) Epileptiform activity in hippocampal slice cultures with normal inhibitory synaptic drive. Neurosci Lett 108: 76–80PubMedCrossRefGoogle Scholar
  39. McCarren M, Alger BE (1985) Use-dependent depression of IPSPs in rat hippocampal pyramidal cells in vitro. J Neurophysiol 53: 557–571PubMedGoogle Scholar
  40. McIntyre DC, Wong RKS (1986) Cellular and synaptic properties of amygdala-kindled pyriform cortex in vitro. J Neurophysiol 55: 1295–1307PubMedGoogle Scholar
  41. Meldrum BS, Croucher MJ, Badman C, Collins JS (1983) Antiepileptic action of excitatory amino acid antagonists in the photosensitive baboon, Papio papio. Neurosci Lett 39: 101–104PubMedCrossRefGoogle Scholar
  42. Mody I, Stanton PK, Heinemann U (1988) Activation of N-methyl-D-aspartate receptors parallels changes in cellular and synaptic properties of dentate gyrus granule cells after kindling. J Neurophysiol 59: 1033–1054PubMedGoogle Scholar
  43. Newberry NR, Nicoll RA (1984) A bicucculine-resistant inhibitory post-synaptic potential in rat hippocampal pyramidal cells in vitro. J Physiol (Lond) 348: 239–254Google Scholar
  44. Noebels JL, Sidman RL (1979) Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science 204: 1334–1336PubMedCrossRefGoogle Scholar
  45. Noebels JL (1984) A single gene error of noradrenergic axon growth synchronizes central neurons. Nature 310: 409–411PubMedCrossRefGoogle Scholar
  46. Noebels JL, Rutecki PA (1990) Altered hippocampal network excitability in the hypernoradrenergic mutant mouse tottering. Brain Res 524: 225–230PubMedCrossRefGoogle Scholar
  47. Olpe H-R (1982) The locus coeruleus as a target for the activating action of vincamine, nicotine and caffeine. Experientia 38: 757Google Scholar
  48. Poolos NP, Mauk MD, Kocsis JD (1987) Activity-evoked increases in extracellular potassium modulate presynaptic excitability in the CA1 region of the hippocampus. J Neurophysiol 58: 404–416PubMedGoogle Scholar
  49. Prince DA, Connors BW (1986) Mechanisms of interictal epileptogenesis. In: DelgadoEsqueta A, et al (eds) Advances in neurology, vol 44. Raven, New York, pp 275–299Google Scholar
  50. Psarropoulou C, Kostopoulos G (1990) Long term enhancement of post synaptic excitability after brief exposure to Mg2+ free medium in normal and epileptic mice. Brain Res 508: 70–75PubMedCrossRefGoogle Scholar
  51. Psarropoulou C, Angelatou F, Matsokis N, Veronikis DK, Kostopoulos G (1987) Absence of modification in GABA and benzodiazepine binding and in choline acetyltransferase activity in brain areas of the epileptic mutant mouse tottering. Gen Pharmacol 18 (6): 593–597PubMedCrossRefGoogle Scholar
  52. Schwartzkroin PA, Prince DA (1980) Changes in excitatory and inhibitory synaptic potentials leading to epileptogenic activity. Brain Res 183: 61–76PubMedCrossRefGoogle Scholar
  53. Shefner SA, Chiu TH (1986) Adenosine inhibits locus coeruleus neurons: an intracellular study in a rat brain slice preparation. Brain Res 366: 364–368PubMedCrossRefGoogle Scholar
  54. Somjen GG (1979) Extracellular potassium in the central nervous system. Ann Rev Physiol 41: 159–177CrossRefGoogle Scholar
  55. Spencer WA, Kandel ER (1969) Synaptic inhibition in seizures. In: Jasper HH, Ward AA, Pope A (eds) Basic mechanisms of the epilepsies. Little, Brown and Co, Boston, pp 575–603Google Scholar
  56. Stanfield BB (1989) Excessive intra-and supragranular mossy fibers in the dentate gyrus of tottering (tg/tg) mice. Brain Res 480: 294–299PubMedCrossRefGoogle Scholar
  57. Tancredi V, Avoli M (1987) Control of spontaneous epileptiform discharges by extracellular potassium. An “in vitro” study in the CA1 subfield of the hippocampal slice. Exp Brain Res 67: 363–372PubMedCrossRefGoogle Scholar
  58. Taylor-Courval D, Gloor P (1984) Behavioural alterations associated with generalized spike and wave discharges in the EEG of the cat. Exp Neurol 83: 167–186PubMedCrossRefGoogle Scholar
  59. Traynellis SF, Dingledine R (1988) Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J Neurophysiol 59 (1): 259–276Google Scholar
  60. Tuff LP, Racine RJ, Adamec R (1983) The effect of kindling on GABA-mediated inhibition in the dentate gyrus of the rat. I. Paired -pulse depression. Brain Res 277: 79–90PubMedCrossRefGoogle Scholar
  61. Vornov JJ, Sutin J (1986) Noradrenergic hyperinnervation of motor trigeminal nucleus: alterations in membrane properties and response to synaptic input. J Neurosci 6 (1): 30–37PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • G. K. Kostopoulos
    • 1
    • 2
  • C. T. Psarropoulou
    • 1
  1. 1.Department of PhysiologyUniversity of Patras Medical SchoolPatrasGreece
  2. 2.Department of PhysiologyUniversity of Patras Medical SchoolPatrasGreece

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