Effects of amyloid-β peptides on the serotoninergic 5-HT1A receptors in the rat hippocampus.
A recent [(18)F]MPPF-positron emission tomography study has highlighted an overexpression of 5-HT(1A) receptors in the hippocampus of patients with mild cognitive impairment compared to a decrease in those with Alzheimer's disease (AD) [Truchot, L., Costes, S.N., Zimmer, L., Laurent, B., Le Bars, D., Thomas-Antérion, C., Croisile, B., Mercier, B., Hermier, M., Vighetto, A., Krolak-Salmon, P., 2007. Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment. Neurology 69 (10), 1012-1017]. We used in vivo and in vitro neuroimaging to evaluate the longitudinal effects of injecting amyloid-β (Aβ) peptides (1-40) into the dorsal hippocampus of rats. In vivo microPET imaging showed no significant change in [(18)F]MPPF binding in the dorsal hippocampus over time, perhaps due to spatial resolution. However, in vitro autoradiography with [(18)F]MPPF (which is antagonist) displayed a transient increase in 5-HT(1A) receptor density 7 days after Aβ injection, whereas [(18)F]F15599 (a radiolabelled 5-HT(1A) agonist) binding was unchanged suggesting that the overexpressed 5-HT(1A) receptors were in a non-functional state. Complementary histology revealed a loss of glutamatergic neurons and an intense astroglial reaction at the injection site. Although a neurogenesis process cannot be excluded, we propose that Aβ injection leads to a transient astroglial overexpression of 5-HT(1A) receptors in compensation for the local neuronal loss. Exploration of the functional consequences of these serotoninergic modifications during the neurodegenerative process may have an impact on therapeutics targeting 5-HT(1A) receptors in AD.
Verdurand
Mathieu
M
Laboratory of Neuropharmacology, FRE CNRS 3006, Univ Lyon 1, Université de Lyon, France.
Bérod
Anne
A
Le Bars
Didier
D
Zimmer
Luc
L
D000409:Alanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography / Q000379:methods; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005462:Fluorine Radioisotopes; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; C101185:alpha-methyl-4-phosphonophenylglycine; C078592:amyloid beta-protein (1-40); D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D000409:Alanine