Mitochondrial Dysfunction Links to Impaired Hippocampal Serotonin Release in a Mouse Model of Alzheimer’s Disease

Background: Deprivation of extracellular serotonin has been linked to cognitive decline and neuropsychiatric disturbances in Alzheimer’s disease (AD). However, despite degeneration of serotonin-producing neurons, whether serotonin release is affected in AD-sensitive brain regions is unknown. Objective: This study investigated the impact of mitochondrial dysfunction in decreased hippocampal serotonin release in AD amyloidosis mouse model 5xFAD mice. Methods: Electrochemical assays were applied to examine hippocampal serotonin release. We also employed multidisciplinary techniques to determine the role of oligomeric amyloid-β (Aβ) in hippocampal mitochondrial deficits and serotonin release deficiency. Results: 5xFAD mice exhibited serotonin release decrease and relatively moderate downregulation of serotonergic fiber density as well as serotonin content in the hippocampal region. Further experiments showed an inhibitory effect of oligomeric amyloid-β (Aβ) on hippocampal serotonin release without affecting the density of serotonergic fibers. Pharmaceutical uncoupling of mitochondrial oxidative phosphorylation (OXPHOS) disrupted hippocampal serotonin release in an ex vivo setting. This echoes the mitochondrial defects in serotonergic fibers in 5xFAD mice and oligomeric Aβ-challenged primary serotonergic neuron cultures and implicates a link between mitochondrial dysfunction and serotonin transmission defects in AD-relevant pathological settings. Conclusion: The most parsimonious interpretation of our findings is that mitochondrial dysfunction is a phenotypic change of serotonergic neurons, which potentially plays a role in the development of serotonergic failure in AD-related conditions.