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.

Aerobic Exercise Improves Methamphetamine-Induced Olfactory Dysfunction Through α-Synuclein Intervention in Male Mice

“…Our electrophysiological results revealed that mitral cells with impaired inhibitory synaptic transmission exhibited higher cluster discharge activity. The increased firing activity of mitral cells induced by Meth is consistent with the result of direct injection of α-syn into the olfactory bulb ( Chen et al, 2021 ), and similar damage to the inhibitory regulation of mitral cells has also been found in other neurodegenerative diseases, such as Alzheimer’s disease (AD) ( Hu et al, 2021 ). Parallel to the results, the inhibitory synaptic transmission manifested by inhibitory postsynaptic currents (IPSCs) was impaired, thus impairing local inhibitory circuits.…”

“…Normal neural activity and synaptic plasticity of mitral cells are required for the efficient performance of olfactory function, and the accumulation of α-syn is tightly coupled with abnormal electrical activity of olfactory neurons ( Chen et al, 2021 ). According to the cell-attached recordings, Meth increased the spontaneous firing rate of mitral cells; this effect could be alleviated by exercise but blocked upon α-syn restoration ( Figures 6A,B ).…”

“…Our findings indicate that the elevation of α-syn is implicated in Meth-induced olfactory dysfunction, and the dysfunction can be alleviated by knockdown of α-syn. Consistently, heterologous injection of α-syn into the olfactory bulb has also been shown to cause abnormalities in olfactory function ( Niu et al, 2018 ; Chen et al, 2021 ); however, the artificial intervention could not mimic the natural process of disease progression. In this study, we demonstrated for the first time that Meth could impair olfactory function by increasing the levels of α-syn in the olfactory bulb; this is a potential pathophysiological mechanism by which Meth abuse influences olfactory function.…”

“…Accumulating studies have revealed that α-syn is involved in maintaining normal synaptic transmission and is implicated in the pathogenesis of synucleinopathies ( Burré et al, 2018 ), and the olfactory bulb is not only the brain region with high expression of α-syn ( Hansen et al, 2013 ) but also the initial site of its propagation to multiple brain regions ( Cersosimo, 2018 ). The accumulation of α-syn in the olfactory bulb is increased during aging and in neurodegenerative diseases ( Bobela et al, 2015 ; Srinivasan et al, 2021 ), and artificial regulation of systemic/brain α-syn expression or direct overexpression of α-syn in the olfactory bulb has been shown to cause olfactory impairment ( Hansen et al, 2013 ; Zhang et al, 2015 ; Chen et al, 2021 ). Notably, a definite association has been found between abnormal metabolism of α-syn and the occurrence of neuropsychiatric symptoms ( Wu et al, 2021 ).…”

Linking α-synuclein-induced synaptopathy and neural network dysfunction in early Parkinson’s disease

“…Emerging evidence from our lab and others links similar disruption in patterns of network oscillations to prodromal symptoms, using the early anatomical target—the olfactory system. 188 , 189 An advantage of using the olfactory system is that the sensory information is monosynaptically conveyed from the OB into down-stream cortices. α-Syn aggregate formation in the OB results in olfactory perceptual dysfunction.…”