ToxSci Advance Access originally published online on August 19, 2009
Toxicological Sciences 2009 112(1):185-195; doi:10.1093/toxsci/kfp196
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Long-term Cognitive Impairments in Adult Rats Treated Neonatally with β-N-Methylamino-L-Alanine
Department of Pharmaceutical Biosciences, Uppsala University, SE-751 24 Uppsala, Sweden
* To whom correspondence should be addressed at Department of Pharmaceutical Biosciences, Uppsala University, Box 594, SE-751 24 Uppsala, Sweden. Fax: +46 18 471-4253. E-mail: eva.brittebo{at}farmbio.uu.se.
Received July 8, 2009; accepted August 10, 2009
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Abstract |
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Most cyanobacteria (blue-green algae) can produce the neurotoxin β-N-methylamino-L-alanine (BMAA). Dietary exposure to BMAA has been suggested to be involved in the etiology of the neurodegenerative disease amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC). Little is known about BMAA-induced neurotoxicity following neonatal administration. Our previous studies have revealed an uptake of BMAA in the hippocampus and striatum of neonatal mice. Furthermore, rats treated with BMAA during the neonatal period displayed acute but transient motoric disturbances and failed to show habituation at juvenile age suggesting impairments in learning functions. In the present study, the aim was to investigate long-term behavioral effects of BMAA administration in neonatal rats. BMAA was administered on postnatal days 9–10 (200 or 600 mg/kg; subcutaneous injection). Spatial learning and memory was investigated in adulthood using the radial arm maze test. The results revealed impaired learning but not memory in BMAA-treated animals. The observed impairments were not due to alterations in motoric capacity, general activity, or behavioral profiles, as assessed in the multivariate concentric square field (MCSF) and open field tests. An aversive stimulus in the MCSF test revealed impairments in avoidance learning and/or memory. There was no difference in basal serum corticosterone levels in BMAA-treated animals, indicating that the observed long-term effects were not secondary to an altered basal hypothalamic-pituitary-adrenal axis function. The present data demonstrated long-term learning impairments following neonatal BMAA administration. Further studies on biochemical effects in various brain regions and subsequent behavioral alterations are needed to elucidate the mechanisms of BMAA-induced developmental neurotoxicity.
Key Words: cyanobacteria; ALS/PDC; brain growth spurt; multivariate concentric square field; behavior; developmental neurotoxicity.