Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice.
Intrahippocampal injections of aggregated amyloid-beta (Abeta)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 Abeta protein, we studied 5-HT2A receptor regulation in double transgenic AbetaPPswe/PS1dE9 mice which display excess production of Abeta 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 Abeta 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 Abeta 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 Abeta accumulation and changes in 5-HT2A receptor expression that is independent of upstream changes in the serotonergic system.
Holm
Peter
P
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Ettrup
Anders
A
Klein
Anders B
AB
Santini
Martin A
MA
El-Sayed
Mona
M
Elvang
Anders B
AB
Stensbøl
Tine B
TB
Mikkelsen
Jens D
JD
Knudsen
Gitte M
GM
Aznar
Susana
S
D000375:Aging / Q000502:physiology; D000662:Amphetamines / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics*; D000814:Aniline Compounds / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D015283:Citalopram / Q000493:pharmacokinetics; D003627:Data Interpretation, Statistical; D005464:Fluorobenzenes / Q000493:pharmacokinetics; D016762:Genes, fos / Q000235:genetics; D019416:Head Movements / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010880:Piperidines / Q000493:pharmacokinetics; D058225:Plaque, Amyloid / Q000473:pathology*; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics* / Q000502:physiology*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics; D013844:Thiazoles / Q000493:pharmacokinetics
D000662:Amphetamines; D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; D015283:Citalopram; D005464:Fluorobenzenes; D007202:Indicators and Reagents; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D013844:Thiazoles; C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; C079049:volinanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine