Amyloid β oligomers disrupt piriform cortical output via a serotonergic pathway

Although olfactory deficits have been found in patients with early-stage Alzheimer's disease (AD), the underlying mechanisms remain unclear. Here we investigated whether and how human amyloid beta (A beta) oligomers affect neural activity in the piriform cortex (PC) slices of adult mice. We found that oligomeric A beta 1-42 decreased the excitability of pyramidal neurons in the anterior PC. The effect was not blocked by glutamate or GABAA receptor antagonists, suggesting that A beta 1-42-induced hypoactivity is indepen-dent of glutamatergic and GABAergic transmission. Interestingly, the hypoexcitability was occluded by serotonin (5-HT) and blocked by antagonists of 5-HT2C receptors, phospholipase C (PLC), and calcium -activated potassium (BK) channels. Furthermore, A beta 1-42 oligomers failed to increase K +-channel currents in the presence of a BK channel blocker. Finally, 5-HT2C receptor antagonist improved olfactory memory and odor discrimination in APP/PS1 mice. The above data indicate that A beta disrupts olfactory informa-tion output from the PC via the 5-HT-5-HT2C receptor-PLC-BK channel pathway. This study reveals that serotonergic modulation is a potential novel therapeutic target for olfactory damage in AD.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

In this study, it was found that human amyloid beta (Aβ) oligomers negatively affect the excitability of pyramidal neurons in the anterior piriform cortex (PC) of adult mice. This effect is independent of glutamatergic and GABAergic transmission, but regulated by serotonin, 5-HT2C receptors, phospholipase C (PLC), and calcium-activated potassium (BK) channels. The findings suggest that serotonergic modulation could be a potential therapeutic target for olfactory damage in Alzheimer's disease.