Kolling, L. J. | Search bioRxiv

bioRxiv2025

Selective reduction of KCNA4 in vulnerable glutamatergic-serotonin neurons of the dorsal raphe nucleus in Alzheimers Disease

INTRODUCTIONWe previously demonstrated that htau mice recapitulate many neuropsychiatric features of early Alzheimers disease (AD), and that the dorsal raphe nucleus (DRN) contains distinct subregions. Herein, we investigate vulnerability of the centromedial DRN to pathologically-phosphorylated tau (pTau), a region composed predominantly of dually serotonergic/glutamatergic (5HT/glut) neurons. METHODSWe use computational, molecular, biophysical, and behavioral techniques to assess the centromedial DRN across preclinical and post-mortem settings. RESULTSThe centromedial DRN contains 5HT/glut neurons that differentially express ion-channel genes in the htau mouse. 5HT/glut neurons exhibit increased excitability, which we demonstrate may dually promote pTau accumulation and the severity of depressive-like behaviors in htau mice. At Braak 2, KCNA4 is reduced in 5HT/glut neurons in AD, which are especially vulnerable to pTau compared to 5HT-nonglut neurons. DISCUSSIONTau-mediated dysfunction of the DRN may be driven by changes in ion channel activity that concomitantly promote the spread of pTau in Braak progression.

neuroscience↗

bioRxiv2025

The superficial tufted and mitral cell output neurons of the mouse olfactory bulb have a dual role in insulin sensing

The olfactory bulb (OB) contains multiple, parallel projection neurons to relay the nature of a stimulus. In a mouse ex vivo slice preparation, we used patch-clamp electrophysiology to measure intrinsic properties, excitability, action potential (AP) shape, voltage-activated conductances, and neuromodulation in the newly-categorized superficial tufted cells (sTCs) compared with those of mitral cells (MCs). We propose that a marked difference in voltage-dependent current represents distinct ion channel populations that affect the kinetics of action potentials, and evokes an increase in sTC firing frequency, albeit both types of projection neurons having similar AP spiking activity. Triple-colored immunofluorescence and RNA scope were used to detect co-localization of the Kv1.3 ion channel and the insulin receptor in sTCs, with [~]73% of sTCs expressing both. The sTCs were modulated by bath application of insulin - increasing AP firing frequency by 97%, attributable to an 8% decrease in the intraburst interval, and a reduction of the latency to first spike by 37%. We conclude that there may be a range of neuromodulators of sTCs that may alter excitability and fine-tune olfactory information processing or metabolic balance. SUMMARY STATEMENTSuperficial tufted cells, as output neurons of the olfactory bulb, were electrophysiologically studied to be insulin sensitive. Brain insulin signaling represents a manner in which olfactory and metabolic circuitry are intertwined.

neuroscience↗