Effects of amyloid-β peptides on the serotoninergic 5-HT1A receptors in the rat hippocampus

A recent [F-18]MPPF-positron emission tomography study has highlighted an overexpression of 5-HT1A 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-Anterion, 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-beta (A beta) peptides (1-40) into the dorsal hippocampus of rats. In vivo microPET imaging showed no significant change in [F-18]MPPF binding in the dorsal hippocampus over time, perhaps due to spatial resolution. However, in vitro autoradiography with [F-18]MPPF (which is antagonist) displayed a transient increase in 5-HT1A receptor density 7 days after A beta injection, whereas [F-18]F15599 (a radiolabelled 5-HT1A agonist) binding was unchanged suggesting that the overexpressed 5-HT1A 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 A beta injection leads to a transient astroglial overexpression of 5-HT1A 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-HT1A receptors in AD. (C) 2009 Elsevier Inc. All rights reserved.