GABAA receptor agonist muscimol rescues inhibitory microcircuit defects in the olfactory bulb and improves olfactory function in APP/PS1 transgenic mice

Olfactory damage develops at the early stages of Alzheimer's disease (AD). While amyloid-beta (A beta) oligomers are shown to impair inhibitory circuits in the olfactory bulb (OB), its underlying mechanisms remain unclear. Here, we investigated the olfactory dysfunction due to impaired inhibitory transmission to mitral cells (MCs) of the OB in APP/PS1 mice. Using electrophysiological studies, we found that MCs ex-hibited increased spontaneous firing rates as early as 3 months, much before development of A beta deposits in the brain. Furthermore, the frequencies but not amplitudes of MC inhibitory postsynaptic currents de-creased markedly, suggesting that presynaptic GABA release is impaired while postsynaptic GABA(A) recep-tor responses remain intact. Notably, muscimol, a GABA(A) receptor agonist, improved odor identification and discrimination behaviors in APP/PS1 mice, reduced MC basal firing activity, and rescued inhibitory circuits along with reducing the A beta burden in the OB. Our study links the presynaptic deficits of GABAer-gic transmission to olfactory dysfunction and subsequent AD development and implicates the therapeutic potential of maintaining local inhibitory microcircuits against early AD progression. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

Olfactory damage occurs early in Alzheimer's disease, potentially related to impaired inhibitory transmission. Experimental evidence suggests that deficits in presynaptic GABAergic transmission may contribute to olfactory dysfunction and the progression of AD.