Low doses of domoic acid during postnatal development produce permanent changes in rat behaviour and hippocampal morphology
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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.
KeywordsBrain development Behaviour Mossy fiber sprouting Neurotrophins Kainate receptors Epilepsy
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- Campochiaro P and JT Coyle (1978) Ontogenetic development of kainate neurotoxicity: correlates with glutamatergic innervation.Neurobiol. 75, 2025–2029.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
- 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
- Paxinos G and C Watson (1986)The Rat Brain in Stereotaxic Coordinates (Academic Press: New York).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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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