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

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 alpha-synuclein is observed in the olfactory bulb (OB) during the early stages of PD, indicating a relationship between alpha-synuclein pathology and hyposmia. Here we investigate whether and how alpha-synuclein aggregates modulate neural activity in the OB at the single-cell and synaptic levels. We induced alpha-synuclein aggregation specifically in the OB via overexpression of double-mutant human alpha-synuclein by an adeno-associated viral (AAV) vector. We found that alpha-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 alpha-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 alpha-synuclein aggregates. These results provide direct evidences of the role of alpha-synuclein aggregates on PD-related olfactory dysfunction and reveal the neural circuit mechanisms by which olfaction is modulated by alpha-synuclein pathology.

Automated summary

The aggregation of alpha-synuclein in the olfactory bulb can impair odor detection and perception in mice, as well as increase the activity of M/Ts cells. This study provides direct evidence of the impact of alpha-synuclein aggregates on olfactory dysfunction in Parkinson's disease and reveals the neural circuit mechanisms involved.