Neurotoxicity Research

, Volume 6, Issue 7–8, pp 555–563 | Cite as

Low doses of domoic acid during postnatal development produce permanent changes in rat behaviour and hippocampal morphology

  • T. A. Doucette
  • P. B. Bernard
  • H. Husum
  • M. A. Perry
  • C. L. Ryan
  • R. A. Tasker


It is well established that the developing brain is a highly dynamic environment that is susceptible to toxicity produced by a number of pharmacological, chemical and environmental insults. We report herein on permanent behavioural and morphological changes produced by exposing newborn rats to very low (subconvulsive) doses of kainate receptor agonists during a critical window of brain development. Daily treatment of SD rat pups with either 5 or 20 µg/kg of domoic acid (DOM) from postnatal day 8-14 resulted in a permanent and reproducible seizure-like syndrome when animals were exposed to different tests of spatial cognition as adults. Similar results were obtained when animals were treated with equi-efficacious doses of kainic acid (KA; 25 or 100 µg/kg). Treated rats had significant increases in hippocampal mossy fiber staining and reductions in hippocampal cell counts consistent with effects seen in adult rats following acute injections of high doses of kainic acid.In situ hybridization also revealed an elevation in hippocampal brain derived neurotrophic factor (BDNF) mRNA in region CA1 without a corresponding increase in neuropeptide Y (NPY) mRNA. These results provide evidence of long-lasting behavioural and histochemical consequences arising from relatively subtle changes in glutamatergic activity during development, that may be relevant to understanding the aetiology of seizure disorders and other forms of neurological disease.


Brain development Behaviour Mossy fiber sprouting Neurotrophins Kainate receptors Epilepsy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ben Ari Y and R Cossart R (2000) Kainate, a double agent that generates seizures: two decades of progress.Trends Neurosci. 23, 580–587.CrossRefGoogle Scholar
  2. Bernard A and M Khrestchatisky (1994) Assessing the extent of RNA editing in the TMII regions of GluR5 and GluR6 kainate receptors during rat brain development.J. Neurochem. 62, 2057–2060.PubMedCrossRefGoogle Scholar
  3. Binder DK, SD Croll, CM Gall and HE Scharfman (2001) BDNF and epilepsy: too much of a good thing?Trend Neurosci. 24, 47–53.PubMedCrossRefGoogle Scholar
  4. Bleakman D and D Lodge (1998) Neuropharmacology of AMPA and kainate receptors.Neuropharmacol. 37, 1187–1204.CrossRefGoogle Scholar
  5. Campochiaro P and JT Coyle (1978) Ontogenetic development of kainate neurotoxicity: correlates with glutamatergic innervation.Neurobiol. 75, 2025–2029.Google Scholar
  6. Chandrasekaran A, G Ponnambalam and C Kaur (2004) Domoic acid-induced neurotoxicity in the hippocampus of adult rats.Neurotoxicity Res. 6, 105–117.Google Scholar
  7. Dai X, LD Lercher, PM Clinton, Y Du, DL Livingston, C Vieira, L Yang, MM Shen and CF Dreyfus (2003) The trophic role of oligodendrocytes in the basal forebrain.J. Neurosci. 23, 5846–5853.PubMedGoogle Scholar
  8. Danzer SC, X He and JO McNamara (2004) Ontogeny of seizureinduced increases in BDNF immunoreactivity and TrkB receptor activation in rat hippocampus.Hippocampus 14, 345–355.PubMedCrossRefGoogle Scholar
  9. Dobbing J and J Sands (1979) Comparative aspects of the brain growth spurt.Early Hum. Dev. 1, 79–83.CrossRefGoogle Scholar
  10. Dobbing J and JL Smart JL (1974) Vulnerability of developing brain and behaviour.Br. Med. Bull. 30, 164–168.PubMedGoogle Scholar
  11. Doucette TA, SM Strain, GV Allen, CL Ryan and RAR Tasker (2000) Comparative behavioural toxicity of domoic acid and kainic acid in neonatal rats.Neurotoxicol. Teratol. 22, 863–869.PubMedCrossRefGoogle Scholar
  12. Doucette TA, PB Bernard, PC Yuill, RA Tasker and CL Ryan (2003) Low doses of non-NMDA glutamate receptor agonists alter neurobehavioural development in the rat.Neurotoxicol. Teratol. 25, 473–479.PubMedCrossRefGoogle Scholar
  13. Galvan CD, RA Hrachovy, KL Smith and JW Swann (2000) Blockade of neuronal activity during hippocampal development produces a chronic focal epilepsy in the rat.J. Neurosci. 20, 2904–2916.PubMedGoogle Scholar
  14. Grigorenko E, S Glazier, W Bell, M Tytell, E Nosel, T Pons and SA Deadwyler (1997) Changes in glutamate receptor subunit composition in hippocampus and cortex in patients with refractory epilepsy.J. Neurol. Sci. 9, 35–45.CrossRefGoogle Scholar
  15. Grigorenko EV, WL Bell, S Glazier, T Pons and S Deadwyler (1998) Editing status at the Q/R site of the GluR2 and GluR6 glutamate receptor subunits in the surgically excised hippocampus of patients with refractory epilepsy.Neuroreport 9, 2219–2224.PubMedCrossRefGoogle Scholar
  16. Holmes GL, JL Thompson, T Marchi and DS Feldman (1988) Behavioural effects of kainic acid administration on the immature brain.Epilepsia 29, 721–730.PubMedCrossRefGoogle Scholar
  17. Holmes GL, JL Gaiarsa, N Chevassus Au Louis and Y Ben Ari (1998) Consequences of neonatal seizures in the rat: morphological and behavioral effects.Ann. Neurol. 44, 845–857.PubMedCrossRefGoogle Scholar
  18. Holmes GL, N Chevassus Au Louis, M Sarkisian and Y Ben Ari (1999) Mossy fiber sprouting following recurrent seizures during early development in rats.J. Comp. Neurol. 404, 537–553.PubMedCrossRefGoogle Scholar
  19. Holmes GL, R Khazipou and Y Ben-Ari (2002) Seizure-induced damage in the developing human: relevance of experimental models.Prog. Brain Res. 135, 321–333.PubMedCrossRefGoogle Scholar
  20. Husum H, JD Mikkelsen and A Mork (1998) Extracellular levels of neuropeptide Y are markedly increased in the dorsal hippocampus of freely moving rats during kainic acid-induced seizures.Brain Res. 781, 351–354.PubMedCrossRefGoogle Scholar
  21. Ishizuka N, J Weber and D Amaral (1990) Organization of intrahippocampal projections originating from CA3 pyramidal cells in the rat.J. Comp. Neurol. 195, 580–623.CrossRefGoogle Scholar
  22. Johansen TH, J Drejer, F Watjen and EO Nielsen (1993) A novel non-NMDA receptor antagonist shows selective displacement of low-affinity [3H]kainate binding.Eur. J. Pharmacol. 246, 195–204.PubMedCrossRefGoogle Scholar
  23. Kant GJ, MH Yen, CP D=Angelo, AJ Brown and T Eggleston (1988) Maze performance: a direct comparison of food vs. water mazes.Pharmacol Biochem Behav. 31, 487–491.PubMedCrossRefGoogle Scholar
  24. Kaufmann W (2000) Developmental neurotoxicity, InThe Handbook of Experimental Animals: The Laboratory Rat (Krinke GJ, Ed.) (Academic Press: New York, NY) pp 227–252.Google Scholar
  25. Larsen PJ, JD Mikkelsen, DS Jessop, HS Chowdrey and SL Lightman (1993) Neuropeptide Y mRNA and immunoreactivity in hypothalamic neuroendocrine neurons: effects of adrenalectomy and chronic osmotic stimulation.J. Neurosci. 13, 1138–1147.PubMedGoogle Scholar
  26. Martinez-Palma L, M Pehar, P Cassina, H Peluffo, R Castellanos, G Anesetti, JS Beckman and L Barbeito (2003) Involvement of nitric oxide on kainite-induced toxicity in oligodendrocyte precursors.Neurotoxicity Res. 5, 399–406.CrossRefGoogle Scholar
  27. McDonald JW and MV Johnston (1990) Physiological and pathophysiological roles of excitatory amino acids during central nervous system development.Brain Res. Brain Res. Rev. 15, 41–70.PubMedCrossRefGoogle Scholar
  28. Morimoto K, M Fahnestock and RJ Racine (2004) Kindling and status epilepticus models of epilepsy: rewiring the brain.Prog. Neurobiol. 73, 1–60.PubMedCrossRefGoogle Scholar
  29. Moser EI (1996) Altered inhibition of dentate granule cells during spatial learning in an exploration task.J. Neurosci. 16, 1247–1259.PubMedGoogle Scholar
  30. Mulle C, A Sailer, I Perez-Otano, H Dickinson-Anson, PE Castillo, I Bureau, C Maron, FH Gage, JR Mann, B Bettler and SF Heinemann (1998) Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice.Nature 392, 601–605.PubMedCrossRefGoogle Scholar
  31. Paxinos G and C Watson (1986)The Rat Brain in Stereotaxic Coordinates (Academic Press: New York).Google Scholar
  32. Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure.Electroencephalogr. Clin. Neurophysiol. 32, 281–294.PubMedCrossRefGoogle Scholar
  33. Rice D and S Barone Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models.Environ. Health Perspect. 108 Suppl 3, 511–533.PubMedCrossRefGoogle Scholar
  34. Ritter LM, DM Vazquez and JH Meador-Woodruff (2002) Ontogeny of ionotropic glutamate receptor subunit expression in the rat hippocampus.Brain Res. Dev. Brain Res. 139, 227–236.PubMedCrossRefGoogle Scholar
  35. Sarkisian MR, P Tandon, Z Liu, Y Yang, A Hori, GL Holmes and CE Stafstrom (1997) Multiple kainic acid seizures in the immature and adult brain: ictal manifestations and long-term effects on learning and memory.Epilepsia 38, 1157–1166.PubMedCrossRefGoogle Scholar
  36. Schreiber SS, G Tocco, I Najim, CE Finch, SA Johnson and M Baudry (1992) Absence of c-fos induction in neonatal rat brain after seizures.Neurosci. Lett. 136, 31–35.PubMedCrossRefGoogle Scholar
  37. Sperber EF, KZ Haas, PK Stanton and SL Moshe (1991) Resistance of the immature hippocampus to seizure-induced synaptic reorganization.Brain Res. Dev. Brain Res. 60, 88–93.PubMedCrossRefGoogle Scholar
  38. Stafstrom CE, JL Thompson and GL Holmes (1992) Kainic acid seizures in the developing brain: status epilepticus and spontaneous recurrent seizures.Brain Res. Dev. Brain Res. 65, 227–236.PubMedCrossRefGoogle Scholar
  39. Stafstrom CE, A Chronopoulos, S Thurber, JL Thompson and GL Holmes (1993) Age dependent cognitive and behavioral deficits after kainic acid seizures.Epilepsia 34, 420–432.PubMedCrossRefGoogle Scholar
  40. Strain SM and RA Tasker (1991) Hippocampal damage produced by systemic injections of domoic acid in mice.Neuroscience 44, 343–352.PubMedCrossRefGoogle Scholar
  41. Takahashi M, S Hayashi, A Kakita, K Wakabayashi, M Fukuda, S Kameyama, R Tanaka, H Takahashi and H Nawa (1999) Patients with temporal lobe epilepsy show an increase in brain-derived neurotropic factor protein and its correlation with neuropeptide Y.Brain Res. 818, 579–582.PubMedCrossRefGoogle Scholar
  42. Tasker RA, SM Strain and J Drejer (1996) Selective reduction in domoic acid toxicityin vivo by a novel non-N-methyl-D-aspartate receptor antagonist.Can. J. Physiol. Pharmacol. 74, 1047–1054.PubMedCrossRefGoogle Scholar
  43. Telfeian AE, HJ Federoff, P Leone, MJ During and A Williamson (2000) Overexpression of GluR6 in rat hippocampus produces seizures and spontaneous nonsynaptic burstingin vitro.Neurobiol. Dis. 7, 362–374.PubMedCrossRefGoogle Scholar
  44. Verdoorn TA, TH Johansen, J Drejer and EO Nielsen (1994) Selective block of recombinant GluR6 receptors by NS-102, a novel non-NMDA receptor antagonist.Eur. J. Pharmacol. 269, 43–49.PubMedCrossRefGoogle Scholar
  45. Vezzani A, T Ravizza, D Moneta, M Conti, A Borroni, M Rizzi, R Samanin and R Maj (1999) Brain-derived neurotrophic factor immunoreactivity in the limbic system of rats after acute seizures and during spontaneous convulsions: temporal evolution of changes as compared to neuropeptide Y.Neuroscience 90, 1445–1461.PubMedCrossRefGoogle Scholar
  46. Vorhees CV (1986) Principles of behavioral teratology. InHandbook of Behavioral Teratology (Riley EP and CV Vorhees, Eds.) (Plenum Press: New York, NY), pp 23–48.Google Scholar
  47. Zetterstrom TS, Q Pei and DG Grahame-Smith (1998) Repeated electroconvulsive shock extends the duration of enhanced gene expression for BDNF in rat brain compared with a single administration.Brain Res. Mol. Brain Res. 57, 106–110.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2004

Authors and Affiliations

  • T. A. Doucette
    • 1
  • P. B. Bernard
    • 2
  • H. Husum
    • 4
  • M. A. Perry
    • 2
  • C. L. Ryan
    • 3
  • R. A. Tasker
    • 2
  1. 1.Department of BiologyUniversity of Prince Edward IslandCharlottetownCanada
  2. 2.Department of Biomedical SciencesUniversity of Prince Edward IslandCharlottetownCanada
  3. 3.Department of PsychologyUniversity of Prince Edward IslandCharlottetownCanada
  4. 4.Neuropsychiatric Laboratory RighshospitaletCopenhagenDenmark

Personalised recommendations