Affiliations: [a] Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark | [b] H. Lundbeck A/S, Valby-Copenhagen, Denmark
Correspondence:
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Correspondence to: Susana Aznar, Ph.D., Neurobiology Research Unit, Copenhagen University Hospital, unit 9201, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: +45 35456701; Fax: +45 3545 6713; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: Intrahippocampal injections of aggregated amyloid-β (Aβ)1-42 in rats result in memory impairment and in reduction of hippocampal 5-HT2A receptor levels. In order to investigate how changes in 5-HT2A levels and functionality relate to the progressive accumulation of Aβ protein, we studied 5-HT2A receptor regulation in double transgenic AβPPswe/PS1dE9 mice which display excess production of Aβ and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3H]-MDL100907, [3H]-escitalopram, and [11C]-PIB autoradiography was performed for measuring 5-HT2A receptor, serotonin transporter (SERT), and Aβ plaque levels in medial prefrontal cortex (mPFC), prefrontal cortex (PFC), frontoparietal cortex (FPC), dorsal and ventral hippocampus, and somatosensory cortex. To investigate 5-HT2A receptor functionality, animals were treated with the 5-HT2A receptor agonist DOI and head-twitch response (HTR) subsequently recorded. Expression level of the immediate early gene c-fos was measured by in situ hybridization. We found that the age-related increase in Aβ plaque burden was accompanied by a significant decrease in 5-HT2A receptor binding in mPFC in the 11-month-old group. The changes in 5-HT2A receptor binding correlated negatively with [11C]-PIB binding and were not accompanied by decreases in SERT binding. Correspondingly, 11-month-old transgenic mice showed diminished DOI-induced HTR and reduced increase in expression of c-fos mRNA in mPFC and FPC. These observations point towards a direct association between Aβ accumulation and changes in 5-HT2A receptor expression that is independent of upstream changes in the serotonergic system.
