Project Summary
In addition to its well-known cognitive deficits, Alzheimer’s disease (AD) is often associated with debilitating
changes in affective behavior, including anxiety, depression and altered social engagement. Mechanistic
connections between the hallmark cytopathologies of AD and neuropsychiatric traits remains poorly defined.
Both AD and mood disorders have been associated with neuroinflammation, with CNS elevations of the major
pro-inflammatory mediator IL-1ß seen in both disorders. We and others have found that serotonin (5-HT)
synthesizing neurons are relatively unique as neuronal sites of expression of the receptor for IL-1ß, IL-1R1.
Serotonergic projections to the hippocampus, a site of significant, inflammatory cytokine-inducing pathology in
AD, are believed to contribute to both cognition and mood. We have shown that serotonergic IL-1R1 activation
leads to rapid elevations in activity of the antidepressant-sensitive 5-HT transporter (SERT), enhancing
clearance of 5-HT and diminishing extracellular 5-HT availability. Others have shown that while AD pathology
extends to forebrain-projecting serotonergic raphe nuclei it also leads to and ectopic expression of SERT by
astrocytes. These combined effects can diminish the capacity for serotonergic signaling, reduced anti-
inflammatory 5-HT stimulation of microglia, further increasing IL-1¿ levels and promoting negative affective
states. In this regard, recent studies have indicated that SERT antagonism by 5-HT-selective reuptake inhibitors
(SSRIs), drugs used to treat affective disorders in AD patients, has been reported to reduce A¿ plaque burden
as well as cognitive deficits in AD. We propose that IL-1ß elevations that arise as a consequence of AD pathology
lead to alterations in 5-HT signaling in the hippocampus via serotonergic IL-1R1 activation, changes that can
accelerate cytopathologies, disrupt the function and plasticity of 5-HT modulated hippocampal circuitry, and
support both affective and cognitive disturbances observed in AD. Here we pursue our hypothesis through a
unique, four-way collaborative project involving an expert in SERT and serotonergic dysfunction (Blakely), an
expert in the evaluation of hippocampal physiology and the study of AD genetic mouse models (Ashery), an
expert in the signaling and functional contributions of IL-1R1s (Quan), and an expert in assessment of the
behavior of genetic mouse models (Hahn). We utilize a conditional strategy to eliminate IL-1¿ signaling
specifically in serotonergic raphe neurons in an AD mouse model (5XFAD), attentive to issues of sex-
dependence. Through our efforts, we will determine whether the biochemical, cellular, physiological and
affective/cognitive disturbances that arise from 5XFAD mutations require IL-1R1 signaling to 5-HT neurons. Data
obtained in this effort can then be extended through more sustained funding to further elucidate the timing,
mechanisms and broader circuit specificities driving, and responding to, these changes.