Plaque Deposition Dependent Decrease in 5-HT2A Serotonin Receptor in A beta PPswe/PS1dE9 Amyloid Overexpressing Mice

Intrahippocampal injections of aggregated amyloid-beta (A beta)(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 A beta protein, we studied 5-HT2A receptor regulation in double transgenic A beta PPswe/PS1dE9 mice which display excess production of A beta 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. [H-3]-MDL100907, [H-3]-escitalopram, and [C-11]-PIB autoradiography was performed for measuring 5-HT2A receptor, serotonin transporter (SERT), and A beta 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 A beta 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 [C-11]-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 A beta accumulation and changes in 5-HT2A receptor expression that is independent of upstream changes in the serotonergic system.