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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor deficits, including bradykinesia, rigidity, resting tremor, and postural instability
After observing that α-synuclein aggregates impaired olfactory-related behaviors and altered the normal neural activity of olfactory bulb (OB) neurons in vivo, both in single cells and at the population level, we further demonstrated that the decreased activity in granule cells (GCs) and impaired inhibitory synaptic transmission are likely responsible for the changes in neural activity induced by α-synuclein aggregation in the OB
Since changes in the paired-pulse depression (PPD) of GABAergic IPSCs indicate a likely presynaptic origin for modulatory effects[28,29], our results suggest that the effects of α-synuclein aggregates on GABAergic inhibition in the OB may have a presynaptic locus in GCs
Summary
Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor deficits, including bradykinesia, rigidity, resting tremor, and postural instability. Previous studies have reported a relationship between α-synuclein aggregates within the OB and the olfactory perceptual deficits in an animal model of PD11–14 They found that aggregated α-synuclein in the OB can impair olfactory neurogenesis[15], maturation of newborn neurons[16,17,18], homeostasis of the cholinergic and dopaminergic systems in the OB13, and neural activity at the network level[19], very few studies have focused on the mechanisms by which α-synuclein aggregates alter neural activity at the single-cell or synaptic level. After observing that α-synuclein aggregates impaired olfactory-related behaviors and altered the normal neural activity of OB neurons in vivo, both in single cells and at the population level, we further demonstrated that the decreased activity in granule cells (GCs) and impaired inhibitory synaptic transmission are likely responsible for the changes in neural activity induced by α-synuclein aggregation in the OB
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