•5HT/glut neurons of the DRN differentially express ion-channel genes in hTau mice and in post-mortem AD. hTau 5HT/glut neurons are more excitable, which increases pTau accumulation, and may drive deficits in social interaction behaviors. In parallel, human 5HT/glut neurons are especially vulnerable to tau pathology.

Persons with Alzheimer’s disease (AD) exhibit social withdrawal and changes in mood prior to cognitive decline. These may be driven by pathological changes in the serotonergic (5-HT) nuclei, particularly the dorsal raphe nucleus (DRN). Using Visium Spatial Gene Expression, we previously determined that the DRN of hTau mice (transgenic model for early AD, Khan 2023) differentially expresses ion-channel genes (Kolling 2025), which regulate the electrical activity of neurons. Hyper-phosphorylated Tau (pTau) disrupts neuronal excitability, which may exacerbate its spread.

 

The mouse DRN contains 5-HT neurons that are dually glutamatergic (5HT/glut)

hTau 5HT/glut differentially express Kcna4

Human 5HT/glut differentially express KCNA4 in Alzheimer’s disease

hTau 5HT/glut have altered biophysical properties and action-potential df/dt

Chronic hyper-excitability affects social behavior and enhances pTau accumulation

Human 5HT/glut are especially vulnerable to pTau and preferentially express KCNA4

Future Direction: Which does pTau change first, gene expression or activity?