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Article

Up and Down γ-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice

by
Rubén Pavia-Collado
1,2,3,4,
Raquel Rodríguez-Aller
5,6,
Diana Alarcón-Arís
1,2,3,
Lluís Miquel-Rio
1,2,3,
Esther Ruiz-Bronchal
1,2,3,
Verónica Paz
1,2,3,
Leticia Campa
1,2,3,
Mireia Galofré
2,7,8,
Véronique Sgambato
9 and
Analia Bortolozzi
1,2,3,*
1
Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain
2
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
3
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, 28029 Madrid, Spain
4
miCure Therapeutics Ltd., Tel Aviv 6423902, Israel
5
CHU de Quebec Research Center, Axe Neurosciences, Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1V 4G2, Canada
6
CERVO Brain Research Centre, Quebec City, QC G1J 2G3, Canada
7
Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedicine, Faculty of Medicine and Health Science, University of Barcelona, 08036 Barcelona, Spain
8
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28029 Madrid, Spain
9
CNRS, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229, 69675 Bron, France
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(3), 1807; https://doi.org/10.3390/ijms23031807
Submission received: 10 January 2022 / Revised: 31 January 2022 / Accepted: 2 February 2022 / Published: 4 February 2022
(This article belongs to the Section Molecular Neurobiology)
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Abstract

The synuclein family consists of α-, β-, and γ-Synuclein (α-Syn, β-Syn, and γ-Syn) expressed in the neurons and concentrated in synaptic terminals. While α-Syn is at the center of interest due to its implication in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, limited information exists on the other members. The current study aimed at investigating the biological role of γ-Syn controlling the midbrain dopamine (DA) function. We generated two different mouse models with: (i) γ-Syn overexpression induced by an adeno-associated viral vector and (ii) γ-Syn knockdown induced by a ligand-conjugated antisense oligonucleotide, in order to modify the endogenous γ-Syn transcription levels in midbrain DA neurons. The progressive overexpression of γ-Syn decreased DA neurotransmission in the nigrostriatal and mesocortical pathways. In parallel, mice evoked motor deficits in the rotarod and impaired cognitive performance as assessed by novel object recognition, passive avoidance, and Morris water maze tests. Conversely, acute γ-Syn knockdown selectively in DA neurons facilitated forebrain DA neurotransmission. Importantly, modifications in γ-Syn expression did not induce the loss of DA neurons or changes in α-Syn expression. Collectively, our data strongly suggest that DA release/re-uptake processes in the nigrostriatal and mesocortical pathways are partially dependent on substantia nigra pars compacta /ventral tegmental area (SNc/VTA) γ-Syn transcription levels, and are linked to modulation of DA transporter function, similar to α-Syn.
Keywords: γ-synuclein; AAV vector; antisense oligonucleotide; cognitive dysfunction; dopamine; motor deficits γ-synuclein; AAV vector; antisense oligonucleotide; cognitive dysfunction; dopamine; motor deficits

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MDPI and ACS Style

Pavia-Collado, R.; Rodríguez-Aller, R.; Alarcón-Arís, D.; Miquel-Rio, L.; Ruiz-Bronchal, E.; Paz, V.; Campa, L.; Galofré, M.; Sgambato, V.; Bortolozzi, A. Up and Down γ-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice. Int. J. Mol. Sci. 2022, 23, 1807. https://doi.org/10.3390/ijms23031807

AMA Style

Pavia-Collado R, Rodríguez-Aller R, Alarcón-Arís D, Miquel-Rio L, Ruiz-Bronchal E, Paz V, Campa L, Galofré M, Sgambato V, Bortolozzi A. Up and Down γ-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice. International Journal of Molecular Sciences. 2022; 23(3):1807. https://doi.org/10.3390/ijms23031807

Chicago/Turabian Style

Pavia-Collado, Rubén, Raquel Rodríguez-Aller, Diana Alarcón-Arís, Lluís Miquel-Rio, Esther Ruiz-Bronchal, Verónica Paz, Leticia Campa, Mireia Galofré, Véronique Sgambato, and Analia Bortolozzi. 2022. "Up and Down γ-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice" International Journal of Molecular Sciences 23, no. 3: 1807. https://doi.org/10.3390/ijms23031807

APA Style

Pavia-Collado, R., Rodríguez-Aller, R., Alarcón-Arís, D., Miquel-Rio, L., Ruiz-Bronchal, E., Paz, V., Campa, L., Galofré, M., Sgambato, V., & Bortolozzi, A. (2022). Up and Down γ-Synuclein Transcription in Dopamine Neurons Translates into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice. International Journal of Molecular Sciences, 23(3), 1807. https://doi.org/10.3390/ijms23031807

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