Alpha-synuclein is strategically positioned for afferent modulation of midbrain dopamine neurons and is essential for cocaine preference

• Published in: Communications biology 2019-11, Vol.2 (1), p.418
• Main Authors: Trubetckaia, Olga, Lane, Ariana E, Qian, Liping, Zhou, Ping, Lane, Diane A
• Format: Article
• Language: English
• ISSN: 2399-3642
• DOI: 10.1038/s42003-019-0651-8

Alpha-synuclein (α-syn) is an abundant neuroprotein elevated in cocaine addicts, linked to drug craving, and recruited to axon terminals undergoing glutamatergic plasticity - a proposed mechanism for substance abuse. However, little is known about normal α-syn function or how it contributes to substance abuse. We show that α-syn is critical for preference of hedonic stimuli and the cognitive flexibility needed to change behavioral strategies, functions that are altered with substance abuse. Electron microscopic analysis reveals changes in α-syn targeting of ventral tegmental area axon terminals that is dependent upon the duration of cocaine exposure. The dynamic changes in presynaptic α-syn position it to control neurotransmission and fine-tune the complex afferent inputs to dopamine neurons, potentially altering functional dopamine output. Cocaine also increases postsynaptic α-syn where it is needed for normal ALIX function, multivesicular body formation, and cocaine-induced exosome release indicating potentially similar α-syn actions for vesicle release pre- and post-synaptically.