Skip to main content
SpringerLink
Log in

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

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ben Ari Y and R Cossart R (2000) Kainate, a double agent that generates seizures: two decades of progress.Trends Neurosci. 23, 580–587.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Binder DK, SD Croll, CM Gall and HE Scharfman (2001) BDNF and epilepsy: too much of a good thing?Trend Neurosci. 24, 47–53.

    Article  PubMed  CAS  Google Scholar 

  • Bleakman D and D Lodge (1998) Neuropharmacology of AMPA and kainate receptors.Neuropharmacol. 37, 1187–1204.

    Article  CAS  Google Scholar 

  • Campochiaro P and JT Coyle (1978) Ontogenetic development of kainate neurotoxicity: correlates with glutamatergic innervation.Neurobiol. 75, 2025–2029.

    CAS  Google Scholar 

  • 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 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Dobbing J and J Sands (1979) Comparative aspects of the brain growth spurt.Early Hum. Dev. 1, 79–83.

    Article  Google Scholar 

  • Dobbing J and JL Smart JL (1974) Vulnerability of developing brain and behaviour.Br. Med. Bull. 30, 164–168.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Holmes GL, JL Thompson, T Marchi and DS Feldman (1988) Behavioural effects of kainic acid administration on the immature brain.Epilepsia 29, 721–730.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Morimoto K, M Fahnestock and RJ Racine (2004) Kindling and status epilepticus models of epilepsy: rewiring the brain.Prog. Neurobiol. 73, 1–60.

    Article  PubMed  CAS  Google Scholar 

  • Moser EI (1996) Altered inhibition of dentate granule cells during spatial learning in an exploration task.J. Neurosci. 16, 1247–1259.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G and C Watson (1986)The Rat Brain in Stereotaxic Coordinates (Academic Press: New York).

    Google Scholar 

  • Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure.Electroencephalogr. Clin. Neurophysiol. 32, 281–294.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Strain SM and RA Tasker (1991) Hippocampal damage produced by systemic injections of domoic acid in mice.Neuroscience 44, 343–352.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biology, University of Prince Edward Island, C1A 4P3, Charlottetown, PE, Canada

    T. A. Doucette

  2. Department of Biomedical Sciences, University of Prince Edward Island, C1A 4P3, Charlottetown, PE, Canada

    P. B. Bernard, M. A. Perry & R. A. Tasker

  3. Department of Psychology, University of Prince Edward Island, C1A 4P3, Charlottetown, PE, Canada

    C. L. Ryan

  4. Neuropsychiatric Laboratory Righshospitalet, DK-220, Copenhagen, Denmark

    H. Husum

Authors
  1. T. A. Doucette
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. B. Bernard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Husum
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. A. Perry
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. L. Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. A. Tasker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. A. Tasker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Doucette, T.A., Bernard, P.B., Husum, H. et al. Low doses of domoic acid during postnatal development produce permanent changes in rat behaviour and hippocampal morphology. neurotox res 6, 555–563 (2004). https://doi.org/10.1007/BF03033451

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033451

Keywords

Search

Navigation