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

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.

Increased Expression of Alpha-, Beta-, and Gamma-Synucleins in Brainstem Regions of a Non-Human Primate Model of Parkinson’s Disease

“…Regarding γ-Syn, its inactivation in mice affects non-motor symptoms (psycho-emotional status and cognitive abilities) and DA transmission [ 68 , 69 ], while its overexpression induces loss of spinal motor neurons [ 51 ]. In agreement, the overexpression of γ-Syn in mouse DA neurons mainly reduces nigrostriatal DA neurotransmission and evokes motor and cognitive deficits [ 52 ]. At the clinical level, somewhat contradictory data were obtained.…”

“…It is able to inhibit α-syn aggregation and reduces α-syn toxicity [ 49 ] but is also able to induce neurotoxicity [ 50 ]. γ-Syn is also associated with neurodegeneration [ 51 ] and is involved in the modulation of DA transmission [ 52 ]. Finally, recent data indicate that β-Syn and γ-Syn are modulators of synaptic vesicle binding of α-Syn [ 53 ].…”

Sex-Related Differences in Voluntary Alcohol Intake and mRNA Coding for Synucleins in the Brain of Adult Rats Prenatally Exposed to Alcohol

“…Relying on data that loss of α-synuclein could contribute to synaptic dysfunction in the aging brain [ 73 ], changes in the expression of β- and γ-synuclein in male PAE offspring can be interpreted as a synergistic effect leading to more pronounced synaptic dysfunction. At the same time, overexpression of γ-synuclein decreases DA neurotransmission in the nigrostriatal and mesocortical pathways, and increased γ-synuclein levels in the midbrain DA system correlated with an impaired cognitive function [ 74 ], which are typical for PAE offspring.…”

Intracerebral administration of a modified antisense oligonucleotide targeting the dopamine system in a mouse model of Parkinson’s disease

“…The protocol describes the specific steps for using an AAV5 construct overexpressing (h)-α-Syn under the chicken-β-actin promoter, intracerebroventricular administration of indatraline-conjugated ASO, and assessment of striatal DA neurotransmission in mice. However, we have also used this protocol with different serotypes of AAVs (AAV1/2, AAV10) and promotors (cytomegalovirus) to overexpress endogenous or human genes in DA or serotonin (5-HT) neurons ( Pavia-Collado et al., 2022 ; Miquel-Rio et al., 2022 ). We have also designed different oligonucleotide sequences conjugated to sertraline (selective 5-HT transporter ligand) or reboxetine (selective norepinephrine-NE transporter ligand) targeting specific genes of monoamine neuron subtypes.…”

“…We have also designed different oligonucleotide sequences conjugated to sertraline (selective 5-HT transporter ligand) or reboxetine (selective norepinephrine-NE transporter ligand) targeting specific genes of monoamine neuron subtypes. Using these tools, we assessed the impact on 5-HT and NE neurotransmission in the prefrontal cortex and hippocampus ( Bortolozzi et al., 2012 , 2021 ; Ferrés-Coy et al., 2016 ; Alarcón-Arís et al., 2018 ; Fullana et al., 2019 ; Pavia-Collado et al., 2022 ).…”