Dopaminergic neurons establish a distinctive axonal arbor with a majority of non‐synaptic terminals

Ducrot, Charles; Bourque, Marie‐Josée; Delmas, Constantin V. L.; Racine, Anne-Sophie; Bello, Dainelys Guadarrama; Delignat-Lavaud, Benoît; Lycas, Matthew D.; Fallon, Aurélie; Michaud-Tardif, Charlotte; Nanni, Samuel Burke; Herborg, Freja; Gether, Ulrik; Nanci, Antonio; Takahashi, Hideto; Parent, Martin; Trudeau, Louis-Éric

doi:10.1096/fj.202100201rr

Cited by 20 publications

(28 citation statements)

References 83 publications

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“…This observation is surprising because on the one hand, DA release in this region is thought to derive mostly from the STD compartment of DA neurons, and on the other hand, Syt1 is typically known as an axon terminal-specific protein. In line with this, previous work in primary DA neurons failed to detect Syt1 immunoreactivity in the cell body and dendrites of DA neurons, with the protein detected in the vast majority of non-synaptic and synaptic terminals along DA neuron axons (Mendez et al, 2011;Ducrot et al, 2021). One possibility is that part of the DA release detected in the VTA and SNc derives from local DA neuron axon collaterals, which would contain Syt1.…”

Section: Discussionsupporting

confidence: 66%

“…Syt1, 2, and 9 were confirmed as calcium sensors for fast synaptic neurotransmitter release from axon terminals (Xu et al, 2007). Syt1 was first shown to play a key role in axonal DA release in primary DA neurons (Mendez et al, 2011) in which it is present at both synaptic and non-synaptic terminals (Ducrot et al, 2021), but most likely absent from dendrites (Mendez et al, 2011). Recent work has confirmed and extended this finding in the intact brain by showing that Syt1 is essential for evoked DA release (Banerjee et al, 2020b).…”

Section: Introductionmentioning

confidence: 92%

“…In line with its high expression and localization in the axonal varicosities of DA neurons, Syt1 is a key regulator of activity-dependent DA release (Mendez et al, 2011;Banerjee et al, 2020b;Ducrot et al, 2021). We generated conditional deletion of Syt1 in DA neurons (Syt1 cKO DA ), by crossing Syt1 lox/lox mice with DAT IREScre mice (Fig.…”

Section: Syt1 Is the Main Calcium Sensor For Fast Axonal Dopamine Releasementioning

confidence: 99%

“…Compatible with such observations, DA is thought to act in the brain as a neuromodulator involved in a form of "volume transmission" and not as a point-to-point fast neurotransmitter (Descarries et al, 1996;Antonopoulos et al, 2002;Descarries et al, 2008;Ducrot et al, 2021). DA release occurs not only from axon terminals in the vast axonal arbors of DA neurons, but also from the neurons' somatodendritic (STD) compartment (Rice and Patel, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice

Delignat-Lavaud

Kano

Ducrot

et al. 2021

Preprint

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Midbrain dopamine (DA) neurons, a population of cells that are critical for motor control, motivated behaviors and cognition, release DA via an exocytotic mechanism from both their axonal terminals and their somatodendritic (STD) compartment. In Parkinson's disease (PD), it is striking that motor dysfunctions only become apparent after extensive loss of DA innervation. Although it has been hypothesized that this resilience is due to the ability of many motor behaviors to be sustained through a basal tone of DA and diffuse transmission, experimental evidence for this is limited. Here we conditionally deleted the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (cKODA mice) to abrogate most activity-dependent axonal DA release in the striatum and mesencephalon, leaving STD DA release intact. Strikingly, Syt1 cKODA mice showed intact performance in multiple unconditioned DA-dependent motor tasks, suggesting that activity-dependent DA release is dispensable for such basic motor functions. Basal extracellular levels of DA in the striatum were unchanged, suggesting that a basal tone of extracellular DA is sufficient to sustain basic movement. We also found multiple adaptations in the DA system of cKODA mice, similar to those happening at early stages of PD. Taken together, our findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 92%

Section: Syt1 Is the Main Calcium Sensor For Fast Axonal Dopamine Releasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice

Delignat-Lavaud

Kano

Ducrot

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Therefore, live-cell functional assays, such as electrophysiology and calcium imaging, combined with pharmacological manipulations are more reliable strategies to assess the mechanism of α-syn regulation of neuronal activity. α-Syn overexpression reduces arborization of dopamine neurons and pretreatment with a D2R agonist partially rescues the detrimental impact of α-syn Dopaminergic neurons have extensive axonal arborizations and large terminal fields [99][100][101] , where one dopamine neuron is estimated to have~245,000 release sites 102,103 . Studies in animal models of PD and postmortem data in human PD 104 show that decreased axonal complexity and dendritic arborization, reduction of the number of axon terminals, and global neuronal size precede neuronal death 77,102,105 .…”

Section: α-Syn Overexpression Increases Intracellular and Extracellular Dopamine Levels And Th Expressionmentioning

confidence: 99%

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

Dagra

Miller

Lin

et al. 2021

npj Parkinsons Dis.

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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.

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Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

et al. 2022

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Background: The accumulation of α-synuclein (α-syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson's disease (PD). Although several aspects linked to α-syn-dependent pathology (concerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α-syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particularly at tardive stages of α-syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression. Objectives: We aimed to determine the consequences of a prolonged α-syn overexpression on somatodendritic morphology and functions of SNpc DA neurons. Methods: We performed immunohistochemistry, stereological DA cell counts, analyses of dendritic arborization, ex vivo patch-clamp recordings, and in vivo DA microdialysis measurements in a 12-to 13-month-old transgenic rat model overexpressing the full-length human α-syn (Snca +/+ ) and age-matched wild-type rats.Results: Aged Snca +/+ rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/ inactivating voltage-gated K + channels and Ca 2+ -and voltage-activated large conductance K + channels. These intrinsic currents underlie the repolarization/ afterhyperpolarization phase of action potentials, thus affecting neuronal excitability. Conclusions: Besides clarifying α-syn-induced pathological landmarks, such evidence reveals compensatory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neurodegeneration.

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Dopaminergic neurons establish a distinctive axonal arbor with a majority of non‐synaptic terminals

Cited by 20 publications

References 83 publications

Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice

Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice

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

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

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