uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino-l-alanine) during the neonatal period
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology, Addiction and Behaviour)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2011 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 219, no 2, 310-320 p.Article in journal (Refereed) Published
Abstract [en]

We have reported previously that exposure to the cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) during the neonatal period causes cognitive impairments in adult rats. The aim of this study was to investigate the long-term effects of neonatal BMAA exposure on learning and memory mechanisms and to identify early morphological changes in the neonatal brain. BMAA was injected subcutaneously in rat pups on postnatal days 9-10. BMAA (50 and 200mg/kg) caused distinct deficits in spatial learning and memory in adult animals but no morphological changes. No impairment of recognition memory was detected, suggesting that neonatal exposure to BMAA preferentially affects neuronal systems that are important for spatial tasks. Histopathological examination revealed early neuronal cell death as determined by TUNEL staining in the hippocampus 24h after a high dose (600mg/kg) of BMAA whereas no changes were observed at lower doses (50 and 200mg/kg). In addition, there was a low degree of neuronal cell death in the retrosplenial and cingulate cortices, areas that are also important for cognitive function. Taken together, these results indicate that BMAA is a developmental neurotoxin inducing long-term changes in cognitive function. The risk posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed.

Place, publisher, year, edition, pages
2011. Vol. 219, no 2, 310-320 p.
Keyword [en]
ALS/PDC, Apoptosis, Behavior, Brain growth spurt, Cyanobacteria, Developmental neurotoxicity, Excitotoxicity, Nonprotein amino acid
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-140782DOI: 10.1016/j.bbr.2011.01.056ISI: 000289703700018PubMedID: 21315110OAI: oai:DiVA.org:uu-140782DiVA: diva2:384376
Available from: 2011-01-09 Created: 2011-01-09 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Distribution and Long-term Effects of the Environmental Neurotoxin β-N-methylamino-L-alanine (BMAA): Brain changes and behavioral impairments following developmental exposure
Open this publication in new window or tab >>Distribution and Long-term Effects of the Environmental Neurotoxin β-N-methylamino-L-alanine (BMAA): Brain changes and behavioral impairments following developmental exposure
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Many cyanobacteria are reported to produce the nonprotein amino acid β-N-methylamino-L-alanine (BMAA). Cyanobacteria are extensively distributed in terrestrial and aquatic environments and recently BMAA was detected in temperate aquatic ecosystems, e.g. the Baltic Sea. Little is known about developmental effects of the mixed glutamate receptor agonist BMAA. Brain development requires an optimal level of glutamate receptor activity as the glutamatergic system modulates many vital neurodevelopmental processes.

The aim of this thesis was to investigate the developmental neurotoxicity of BMAA, and its interaction with the pigment melanin. Autoradiography was utilized to determine the tissue distribution of 3H-labelled BMAA in experimental animals. Behavioral studies and histological techniques were used to study short and long-term changes in the brain following neonatal exposure to BMAA. Long-term changes in protein expression in the brain was also investigated using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS).

A notable targeting of 3H-BMAA to discrete brain regions e.g. hippocampus and striatum in mouse fetuses and neonates was determined by autoradiography. BMAA treatment of neonatal rats on postnatal days 9–10 induced acute but transient ataxia and hyperactivity. Postnatal exposure to BMAA also gave rise to reduced spatial learning and memory abilities in adulthood. Neonatal rat pups treated with BMAA at 600 mg/kg showed early neuronal cell death in the hippocampus, retrosplenial and cingulate cortices. In adulthood the CA1 region of the hippocampus displayed neuronal loss and astrogliosis. Lower doses of BMAA (50 and 200 mg/kg) caused impairments in learning and memory function without any acute or long-term morphological changes in the brain. The MALDI IMS studies, however, revealed changes in protein expression in the hippocampus and striatum suggesting more subtle effects on neurodevelopmental processes. The studies also showed that BMAA was bound and incorporated in melanin and neuromelanin, suggesting that pigmented tissues such as in the substantia nigra and eye may be sequestering BMAA.

In conclusion, the findings in this thesis show that BMAA is a developmental neurotoxin in rodents. The risks posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 134
Keyword
ALS/PDC, Guam, Developmental neurotoxicity, Brain growth spurt, Behavior, Nonprotein amino acid, Excitotoxic, Cyanobacteria, Apoptosis, BMAA, environmental toxin, Algal blooming, Algblomning, algtoxin, alggift, hjärnutveckling
National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
urn:nbn:se:uu:diva-140785 (URN)978-91-554-7984-8 (ISBN)
Public defence
2011-02-18, Sal C8:301 Biomedicinskt Centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-01-28 Created: 2011-01-09 Last updated: 2011-03-11Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Karlsson, OskarRoman, ErikaBrittebo, Eva

Search in DiVA

By author/editor
Karlsson, OskarRoman, ErikaBrittebo, Eva
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Behavioural Brain Research
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 745 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf