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 β (Aβ) oligomers affect neural activity in the piriform cortex (PC) slices of adult mice. We found that oligomeric Aβ1-42 decreased the excitability of pyramidal neurons in the anterior PC. The effect was not blocked by glutamate or GABA_A receptor antagonists, suggesting that Aβ1-42-induced hypoactivity is independent of glutamatergic and GABAergic transmission. Interestingly, the hypoexcitability was occluded by serotonin (5-HT) and blocked by antagonists of 5-HT_2C receptors, phospholipase C (PLC), and calcium-activated potassium (BK) channels. Furthermore, Aβ1-42 oligomers failed to increase K⁺-channel currents in the presence of a BK channel blocker. Finally, 5-HT_2C receptor antagonist improved olfactory memory and odor discrimination in APP/PS1 mice. The above data indicate that Aβ disrupts olfactory information output from the PC via the 5-HT-5-HT_2C receptor-PLC-BK channel pathway. This study reveals that serotonergic modulation is a potential novel therapeutic target for olfactory damage in AD.