\u03b1-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

Abeer Dagra,Mengfei Bu,Zachary A Sorrentino,Brittany Ulm,Nikhil Urs,Adithya Gopinath,Joseph J Lebowitz,Adetola R Alonge,Douglas R Miller,Sophia Velasco,Fatemeh Shaerzadeh,Sharonda Harris,Jonatan Fullerton Støier,Benoit I Giasson,Janelle Azar,Habibeh Khoshbouei,Carissa A Hansen,Min Lin

doi:10.1038/s41531-021-00210-w

Abeer Dagra, Mengfei Bu + Show 16 more

Open Access

https://doi.org/10.1038/s41531-021-00210-w

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Abstract

Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

Highlights

Volitional movement is a fundamental behavior of everyday life that is often taken for granted until control deteriorates.Dopaminergic neurons within the ventral midbrain play a critical role in the initiation and control of volitional movement[1,2] and the progressive demise of these neurons is a defining hallmark of Parkinson’s disease (PD)[3]
We demonstrated that D2 receptor (D2R) autoinhibition contributes to alterations in neuronal homeostatic properties and that modulation thereof can ameliorate the pathophysiology resulting from excessive α-syn levels
We previously reported that α-syn overexpression decreases dopamine uptake via the DAT75 and we have reported that α-syn overexpression increases the dopamine transporter (DAT)-mediated dopamine efflux[24]

Summary

INTRODUCTION

Volitional movement is a fundamental behavior of everyday life that is often taken for granted until control deteriorates. The location of midbrain dopamine neurons in deep neural structures creates a significant barrier of investigation and control over the experimental milieu For these reasons, we incorporated a primary culture model system of dopaminergic neurons, which provides unparalleled access and control over the experimental procedure to investigate potential mechanisms of how excessive α-syn level alters dopaminergic neuronal dynamics and dopamine transmission prior to neuronal demise. We demonstrated that D2 receptor (D2R) autoinhibition contributes to alterations in neuronal homeostatic properties and that modulation thereof can ameliorate the pathophysiology resulting from excessive α-syn levels.

RESULTS AND DISCUSSION

METHODS

Dagra et al 17