Serotonin fibre sprouting and increase in serotonin transporter immunoreactivity in the CA1 area of hippocampus in a mouse model of Alzheimer’s Disease is concomitant with an increase in serotonergic axons and terminals: A light and electron microscopic study

Background:Alzheimer’s disease (AD) is a progressive neurodegenerative disease that deteriorates cognitive functions and associated brain regions such as the hippocampus, being the primary cause of dementia. Serotonin (5-HT) widely distributed throughout the hippocampus, is a key neurotransmitter in learning and memory processes. Alterations in 5-HT neurotransmission have been recently implicated in AD, however, it is not clear how hippocampal 5-HT innervation is modified.Methods:We studied the hippocampal 5-HT input by analyzing (i) the expression, density and distribution of serotonin transporter immunoreactive fibres (SERT-IRF); (ii) the specific morphological characteristics of serotonergic fibres and their relation to amyloid plaques; (iii) the distribution and synaptic connectivity of serotonergic terminals and unmyelinated axons (SERT-Te/Ax) and (iv) the total number of serotonin neurones within the raphe nuclei in the triple transgenic mouse model of Alzheimer’s disease (3xTg-AD). We used quantitative light and electron microscopy immunohistochemistry to analyze the differences between 3xTg-AD and non-transgenic animals (non-Tg) at different ages (3, 6, 9, 12 and 18 months).Results:3xTg-AD showed a significant increase in SERT-IRF density in the hippocampus in a subfield, strata and age specific manner. The increase in SERT-IRF was specific to the CA1 stratum lacunosum moleculare. Increase in SERT-IRF in 3xTg-AD was observed at 3 months (61%) and at 18 months (74%) when compared to non-Tg. Increased SERT-IRF density was more pronounced adjacent to amyloid plaques. Ultrastructural studies also revealed that the 3xTg-AD animals have an specific concomitant increase of SERT-Te/Ax in the CA1. This Increase in SERT- Te/Ax in transgenic animals was observed also at 3 months (146 %) and at 18 months (153 %) of non-Tg values. In addition, SERT- Te/Ax had a significant increased surface area these ages (67% and 50% respectively). However, no changes were found in the total number of raphe serotonin neurones at any age.Conclusions:Our results indicate that triple transgenic mice display increased SERT-IRF sprouting and increased SERT-Te density which may account for imbalanced serotonergic neurotransmission associated with Alzheimer’s disease cognitive impairment.