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α-Synuclein aggregation in the olfactory bulb induces olfactory deficits by perturbing granule cells and granular-mitral synaptic transmission.


ABSTRACT: Olfactory dysfunction is an early pre-motor symptom of Parkinson's disease (PD) but the neural mechanisms underlying this dysfunction remain largely unknown. Aggregation of α-synuclein is observed in the olfactory bulb (OB) during the early stages of PD, indicating a relationship between α-synuclein pathology and hyposmia. Here we investigate whether and how α-synuclein aggregates modulate neural activity in the OB at the single-cell and synaptic levels. We induced α-synuclein aggregation specifically in the OB via overexpression of double-mutant human α-synuclein by an adeno-associated viral (AAV) vector. We found that α-synuclein aggregation in the OB decreased the ability of mice to detect odors and to perceive attractive odors. The spontaneous activity and odor-evoked firing rates of single mitral/tufted cells (M/Ts) were increased by α-synuclein aggregates with the amplitude of odor-evoked high-gamma oscillations increased. Furthermore, the decreased activity in granule cells (GCs) and impaired inhibitory synaptic function were responsible for the observed hyperactivity of M/Ts induced by α-synuclein aggregates. These results provide direct evidences of the role of α-synuclein aggregates on PD-related olfactory dysfunction and reveal the neural circuit mechanisms by which olfaction is modulated by α-synuclein pathology.

SUBMITTER: Chen F 

PROVIDER: S-EPMC8668919 | biostudies-literature |

REPOSITORIES: biostudies-literature

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2023-03-27 | PXD040392 | Pride