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

ABSTRACT: Alpha-synuclein (?-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 ?-syn function or how it contributes to substance abuse. We show that ?-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 ?-syn targeting of ventral tegmental area axon terminals that is dependent upon the duration of cocaine exposure. The dynamic changes in presynaptic ?-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 ?-syn where it is needed for normal ALIX function, multivesicular body formation, and cocaine-induced exosome release indicating potentially similar ?-syn actions for vesicle release pre- and post-synaptically.

SUBMITTER: Trubetckaia O

PROVIDER: S-EPMC6858354 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Trubetckaia Olga O Lane Ariana E AE Qian Liping L Zhou Ping P Lane Diane A DA

Communications biology 20191115

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. Elec ...[more]

PMID: 31754648

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Project description:Dopamine (DA) neurons of the ventral tegmental area (VTA) continue to gain attention as far more heterogeneous than previously realized. Within the medial aspect of the VTA, the unexpected presence of TrpV1 mRNA has been identified. TrpV1 encodes the Transient Receptor Potential cation channel subfamily V member 1, TRPV1, also known as the capsaicin receptor, well recognized for its role in heat and pain processing by peripheral neurons. In contrast, the brain distribution of TrpV1 has been debated. Here, we hypothesized that the TrpV1+ identity defines a distinct subpopulation of VTA DA neurons. To explore these brain TrpV1+ neurons, histological analyses and Cre-driven mouse genetics were employed. TrpV1 mRNA was most strongly detected at the perinatal stage forming a band of scattered neurons throughout the medial VTA, reaching into the posterior hypothalamus. Within the VTA, the majority of TrpV1 co-localized with both Tyrosine hydroxylase (Th) and Vesicular monoamine transporter 2 (Vmat2), confirming a DA phenotype. However, TrpV1 also co-localized substantially with Vesicular glutamate transporter 2 (Vglut2), representing the capacity for glutamate (GLU) release. These TrpV1+/Th+/Vglut2+/Vmat2+ neurons thus constitute a molecularly and anatomically distinct subpopulation of DA-GLU co-releasing neurons. To assess behavioral impact, a TrpV1 Cre -driven strategy targeting the Vmat2 gene in mice was implemented. This manipulation was sufficient to alter psychomotor behavior induced by amphetamine. The acute effect of the drug was accentuated above control levels, suggesting super-sensitivity in the drug-na ve state resembling a "pre-sensitized" phenotype. However, no progressive increase with repeated injections was observed. This study identifies a distinct TrpV1+ VTA subpopulation as a critical modulatory component in responsiveness to amphetamine. Moreover, expression of the gene encoding TRPV1 in selected VTA neurons opens up for new possibilities in pharmacological intervention of this heterogeneous, but clinically important, brain area.

Dataset Information

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

Publications

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

Similar Datasets

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