Selective reduction of KCNA4 in vulnerable glutamatergic-serotonin neurons of the dorsal raphe nucleus in Alzheimer's disease

Introduction: Our previous studies demonstrate that htau mice recapitulate many of the neuropsychiatric features of early Alzheimer's disease (AD), and that the dorsal raphe nucleus (DRN) contains distinct subregions. Herein, we investigate the vulnerability of the centromedial DRN to pathologically phosphorylated tau (p-tau), a region composed predominantly of dually serotonergic/glutamatergic (5HT/glut) neurons. Methods: We use a battery of computational, molecular, biophysical, and behavioral techniques to assess molecular changes in the centromedial DRN across preclinical and post mortem settings. Results: The centromedial DRN contains 5HT/glut neurons that differentially express ion-channel genes in the htau mouse. This is associated with increased neuronal excitability, which may promote p-tau accumulation. At Braak II, KCNA4 is reduced in 5HT/glut neurons in AD, which are especially vulnerable to p-tau compared to 5HT-nonglut neurons. Discussion: Tau-mediated dysfunction of the DRN may be driven by changes in ion channel activity that concomitantly promote the spread of p-tau in Braak progression.