Journal
NPJ PARKINSONS DISEASE
Volume 7, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41531-021-00259-7
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Funding
- National Natural Science Foundation of China (NSFC) [31872771, 32070995]
- Natural Science Foundation of the Jiangsu Higher Education Institutions of China [18KJD310006]
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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.
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.
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