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Vol. 21, No. 3-5, 1999
Issue release date: May–October 1999 (November 1999)
Dev Neurosci 1999;21:393–399

Electrophysiological Observations in Hippocampal Slices from Rats Treated with the Ketogenic Diet

Stafstrom C.E. · Wang C. · Jensen F.E.
aDepartment of Neurology, Children’s Hospital, Harvard Medical School, and bDivision of Pediatric Neurology, New England Medical Center, Tufts University School of Medicine, Boston, Mass., USA

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The electrophysiological effects of the high-fat, low-carbohydrate ketogenic diet (KD) were assessed in normal and epileptic [kainic-acid(KA)-treated] adult rats using hippocampal slices. In the first set of experiments, normal rats were fed the KD or a standard control diet for 6–8 weeks (beginning on postnatal day 56, P56), after which they were sacrificed for hippocampal slices. All rats on the KD became ketotic. The baseline effects of the KD were determined by comparing extracellular measures of synaptic transmission and responses to evoked stimulation, and hippocampal excitability was tested in Mg2+-free medium. There were no differences in EPSP slope, input/output relationship, responses to evoked stimulation or Mg2+-free burst frequency between slices from control and KD-fed rats. In another set of experiments, rats were made epileptic by intraperitoneal injection of kainic acid (KA) on P54, which caused status epilepticus followed by the development of spontaneous recurrent seizures (SRS) over the next few weeks. Two days after KA-induced status, rats were divided into a control-fed group and a KD-fed group. Animals on the KD had significantly fewer SRS over the ensuing 8 weeks. In hippocampal slices from KA-treated, KD-fed rats, there were fewer evoked CA1 population spikes than from slices of control-fed rats. These results suggest that the KD does not alter baseline electrophysiological parameters in normal rats. In rats made chronically epileptic by administration of KA, KD treatment was associated with fewer spontaneous seizures and reduced CA1 excitability in vitro. Therefore, at least part of the KD mechanism of action may involve long-term changes in network excitability.

Copyright © 1999 S. Karger AG, Basel

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  1. Appleton DB, DeVivo DC (1974): An animal model for the ketogenic diet. Epilepsia 15:211–217.
  2. Ben-Ari Y (1985): Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375–403.
  3. Bough KJ, Eagles DA (1999): A ketogenic diet increases the resistance to pentylenetetrazole-induced seizures in the rat. Epilepsia 40:138–143.
  4. Brunengraber H (1997): Potential of ketone body esters for parenteral and oral nutrition. Nutrition 13:233–235.
  5. Buckmaster PF, Dudek FE (1997): Network properties of the dentate gyrus in epileptic rats with hilar neuron loss and granule cell axon reorganization. J Neurophysiol 77:2685–2696.
  6. Cavalheiro EA, Riche DA, Le Gal La Salle G (1982): Long-term effects of intrahippocampal kainic acid injection is rats: A method for inducing spontaneous recurrent seizures. Electroencephalogr Clin Neurophysiol 53:581–589.
  7. Cronin J, Dudek FE (1988): Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res 474:181–184.
  8. DeVivo DC, Leckie MP, Ferrendelli JS, McDougal DB (1978): Chronic ketosis and cerebral metabolism. Ann Neurol 3:331–337.
  9. Dudek FE, Spitz M (1997): Hypothetical mechanisms for the cellular and neurophysiologic basis of secondary epileptogenesis: Proposed role of synaptic reorganization. J Clin Neurophysiol 14:90–101.
  10. Freeman JM, Vining EPG, Pillas DJ, Pyzik PL, Casey JC, Kelly MT (1998a): The efficacy of the ketogenic diet – 1998: A prospective evaluation of intervention in 150 children. Pediatrics 102:1358–1363.
  11. Freeman JM, Vining EPG, Pyzik PL, Gilbert DL (1998b): Beta-hydroxybutyrate levels in blood correlate with seizure control in children on the ketogenic diet. Epilepsia 39(suppl 6):167.
  12. Ge S, Niesen CE (1998): Beta-hydroxybutyrate potentiates GABAA mediated inhibitory postsynaptic potentials in immature hippocampal CA1 neurons. Epilepsia 39(suppl 6):135.
  13. Hawkins RA, Williamson DH, Krebs HA (1971): Ketone-body utilization by adult and suckling rat brain in vivo. Biochem J 122:13–18.
  14. Hori A, Tandon P, Holmes GL, Stafstrom CE (1997): Ketogenic diet: Effects on expression of kindled seizures and behavior in adult rats. Epilepsia 38:750–758.
  15. Huttenlocher PR (1976): Ketonemia and seizures: Metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy. Pediatr Res 10:536–540.
  16. Jensen FE, Wang C, Stafstrom CE, Liu Z, Geary C, Stevens MC (1998): Acute and chronic increases in excitability in rat hippocampal slices after perinatal hypoxia in vivo. J Neurophysiol 79:73–81.
  17. Kraus H, Schlenker S, Schwedesky D (1974): Developmental changes of cerebral ketone body utilization in human infants. Hoppe-Seyler’s Z Physiol Chem 355:164–170.
  18. Lustig S, Niesen CE (1998): Beta-hydroxybutyrate suppresses pentylenetetrazol (PTZ)-induced seizures in young adult rats. Epilepsia 39(suppl 6):36.
  19. Mathern GW, Bertram EH, Babb TL, Pretorius JK, Kuhlman PA, Spradlin S, Mendoza D (1997): 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 GABAA receptors. Neuroscience 77:1003–1019.
  20. Mathern GW, Cifuentes F, Leite JP, Pretorius JK, Babb TL (1993): Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model. Electroencephalogr Clin Neurophysiol 87:326–339.
  21. Meier CL, Dudek FE (1996): Spontaneous and stimulation-induced synchronized burst afterdischarges in the isolated CA1 of kainate-treated rats. J Neurophysiol 76:2231–2239.
  22. Muller-Schwarze AB, Sarkisian MR, Yang Y, Tandon P, Liu Z, Holmes GL, Stafstrom CE (1998): Ketogenic diet retards epileptogenesis in the kainic acid model. Epilepsia 39:33.
  23. Muller-Schwarze AB, Tandon P, Liu Z, Yang Y, Holmes GL, Stafstrom CE (1999): Ketogenic diet reduces spontaneous seizures and mossy fiber sprouting in the kainic acid model. Neuroreport 10:1517–1522.
  24. Nakazawa M, Kodama S, Matsuo T (1983): Effects of ketogenic diet on electroconvulsive threshold and brain contents of adenosine nucleotides. Brain Dev 5:375–380.
  25. Niesen CE, Ge S (1998): The effect of ketone bodies, beta-hydroxybutyrate and acetoacetate on acute seizure activity in hippocampal CA1 neurons. Epilepsia 39(suppl 6):35.
  26. Nordli DR, De Vivo DC (1997): The ketogenic diet revisited: Back to the future. Epilepsia 38:743–749.
  27. Perez Y, Morin F, Beaulieu C, Lacaille JC (1996): Axonal sprouting of CA1 pyramidal cells in hyperexcitable hippocampal slices of kainic acid-treated rats. Eur J Neurosci 8:736–748.
  28. Prasad AN, Stafstrom CE, Holmes GL (1996): Alternative epilepsy therapies: The ketogenic diet, immunoglobulins, and steroids. Epilepsia 37(suppl 2): S81–S95.

    External Resources

  29. Racine RJ (1972): Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32:281–294.
  30. Stafstrom CE (1999): Animal models of the ketogenic diet: What have we learned, what can we learn? Epilepsy Res, in press.
  31. Stafstrom CE, Chronopoulos A, Thurber S, Thompson JL, Holmes GL (1993): Age-dependent cognitive and behavioral deficits after kainic acid seizures. Epilepsia 34:420–435.
  32. Tauck DL, Nadler JV (1985): Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci 5:1016–1022.
  33. Uhlemann ER, Neims AH (1972): Anticonvulsant properties of the ketogenic diet in mice. J Pharmacol Exp Ther 180;231–238.
  34. Vining EPG, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, Shinnar S, Shuman R, Trevathan E, Wheless JW (1998): A multicenter study of the efficacy of the ketogenic diet. Arch Neurol 55:1433–1437.
  35. Wilder RM (1921): The effects of ketonemia on the course of epilepsy. Mayo Clin Proc 2:307–308.
  36. Withrow CD (1980): The ketogenic diet. Mechanisms of anticonvulsant action; in Glaser GH, Penry JK, Woodbury WM (eds): Antiepileptic Drugs: Mechanisms of Action, New York, Raven Press, pp 635–642.
  37. Wuarin JP, Dudek FE (1996): Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippcampal slices from kainate-treated epileptic rats. J Neurosci 16:4438–448.

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