GABAA receptor agonist muscimol rescues inhibitory microcircuit defects in the olfactory bulb and improves olfactory function in APP/PS1 transgenic mice.
Neurobiol Aging
; 108: 47-57, 2021 12.
Article
in En
| MEDLINE
| ID: mdl-34507271
ABSTRACT
Olfactory damage develops at the early stages of Alzheimer's disease (AD). While amyloid-ß (Aß) 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 exhibited increased spontaneous firing rates as early as 3 months, much before development of Aß deposits in the brain. Furthermore, the frequencies but not amplitudes of MC inhibitory postsynaptic currents decreased markedly, suggesting that presynaptic GABA release is impaired while postsynaptic GABAA receptor responses remain intact. Notably, muscimol, a GABAA 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 Aß burden in the OB. Our study links the presynaptic deficits of GABAergic transmission to olfactory dysfunction and subsequent AD development and implicates the therapeutic potential of maintaining local inhibitory microcircuits against early AD progression.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Olfactory Bulb
/
Smell
/
Receptors, GABA-A
/
Synaptic Transmission
/
GABA-A Receptor Agonists
/
Olfaction Disorders
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Neurobiol Aging
Year:
2021
Document type:
Article
Affiliation country:
China