Fine tune control of dopamine neurotransmission by alpha-synuclein: down- and over-expression models

Póster presentado en el IX Simposi de Neurobiologia Experimental, celebrado los días 22 y 23 de octubre de 2014 en Barcelona y organizado por la Societat Catalana de Biologia del Institut d'Estudis CatalansAlpha-synuclein protein (α-syn) accumulates in the brain of patients with Parkinson´s disease (PD) and leaves a degeneration of midbrain dopamine (DA) neurons. However, the normal function of α-syn on DA neurotransmission in vivo remains poorly understood. Here, we used two mouse models with a) reduced α-syn expression in the substantia nigra compacta (SNc) and ventral tegmental area (VTA) induced by antisense oligonucleotide molecule (ASO) and, b) modest α-syn over-expression in tyrosine hydroxylase (TH)-positive neurons in the absence of overt toxicity. ASO sequence against α-syn was conjugated to a cell-specific ligand, indatraline (monoamine transporter inhibitor), to promote its selective delivery into monoamine neurons after intranasal administration. Indatraline-α-syn-ASO conjugate (1233ASO) entered into midbrain DA cells followed by trafficking to deep endomembrane vesicles associated with Rab7 resulting in an efficient α-syn knockdown. Indeed, 4-day 1233ASO treatment (30µg/day) decreased α-syn mRNA and protein levels in SNc/VTA (84.1±1.7% and 57.7±7.8% of PBS-treated animals, respectively). Alpha-synuclein suppression displayed an enhancement striatal DA tone using intracerebral microdialysis. Local veratridine (50 µM) perfusion increased extracellular DA levels more efficient in 1233ASO-treated than PBS-treated mice. Similarly, nomifensine (1-10-50 µM) or amphetamine (1-10-100 µM) showed a marked doseeffect which phenotypic differences. Tetrabenazine (VMAT2 inhibitor, 100 µM) reduced striatal DA levels in 1233ASO-treated mice. This effect was lower than in control mice. Conversely, we found that over-expressed α-syn inhibits striatal DA release. Together, this evidence indicates a physiological role for a-syn as a >fine tune> modulator of nigroestriatal DA release and the effects depend on the a-syn expression levelsSpanish Ministery of Economy and Competitiveness, INNPACTO Subprogram IPT-2012-1208-300000; Instituto de Salud Carlos III (ISCIII) Grant PI13/01390. Some of these grants are co-financed by the European Regional Development Fund “A way to build Europe”Peer Reviewe