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A synaptomic analysis reveals dopamine hub synapses in the mouse striatum.

ABSTRACT: Dopamine transmission is involved in reward processing and motor control, and its impairment plays a central role in numerous neurological disorders. Despite its strong pathophysiological relevance, the molecular and structural organization of the dopaminergic synapse remains to be established. Here, we used targeted labelling and fluorescence activated sorting to purify striatal dopaminergic synaptosomes. We provide the proteome of dopaminergic synapses with 57 proteins specifically enriched. Beyond canonical markers of dopamine neurotransmission such as dopamine biosynthetic enzymes and cognate receptors, we validated 6 proteins not previously described as enriched. Moreover, our data reveal the adhesion of dopaminergic synapses to glutamatergic, GABAergic or cholinergic synapses in structures we named "dopamine hub synapses". At glutamatergic synapses, pre- and postsynaptic markers are significantly increased upon association with dopamine synapses. Dopamine hub synapses may thus support local dopaminergic signalling, complementing volume transmission thought to be the major mechanism by which monoamines modulate network activity.

SUBMITTER: Paget-Blanc V

PROVIDER: S-EPMC9166739 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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A synaptomic analysis reveals dopamine hub synapses in the mouse striatum.

Paget-Blanc Vincent V Pfeffer Marlene E ME Pronot Marie M Lapios Paul P Angelo Maria-Florencia MF Walle Roman R Cordelières Fabrice P FP Levet Florian F Claverol Stéphane S Lacomme Sabrina S Petrel Mélina M Martin Christelle C Pitard Vincent V De Smedt Peyrusse Véronique V Biederer Thomas T Perrais David D Trifilieff Pierre P Herzog Etienne E

Nature communications 20220603 1

Dopamine transmission is involved in reward processing and motor control, and its impairment plays a central role in numerous neurological disorders. Despite its strong pathophysiological relevance, the molecular and structural organization of the dopaminergic synapse remains to be established. Here, we used targeted labelling and fluorescence activated sorting to purify striatal dopaminergic synaptosomes. We provide the proteome of dopaminergic synapses with 57 proteins specifically enriched. B ...[more]

PMID: 35660742

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Project description:Dopamine D2 and D3 autoreceptors are located on pre-synaptic terminals and are known to control the release and synthesis of dopamine. Dopamine D3 receptors have a fairly restricted pattern of expression in the mammalian brain. Their localization in the nucleus accumbens core and shell is of particular interest because of their association with the rewarding properties of drugs of abuse. Using background subtracted fast scan cyclic voltammetry, we investigated the effects of dopamine D2 and D3 agonists on electrically stimulated dopamine release and uptake rates in the mouse caudate-putamen and nucleus accumbens core and shell. The dopamine D2 agonists (-)-quinpirole hydrochloride and 5,6,7,8-Tetrahydro-6-(2-propen-1-yl)-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride (B-HT 920) had the same dopamine release inhibition effects on caudate-putamen and nucleus accumbens (core and shell) based on their EC(50) and efficacies. This suggests that the dopamine D2 autoreceptor functionality is comparable in all three striatal regions investigated. The dopamine D3 agonists (4aR,10bR)-3,4a,4,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride ((+)-PD 128907) and (+/-)-7-Hydroxy-2-dipropylaminotetralin hydrobromide (7-OH-DPAT) had a significantly greater effect on dopamine release inhibition in the nucleus accumbens shell than in caudate-putamen. This study confirms that, the dopamine D3 autoreceptor functionality is greater in the nucleus accumbens shell followed by the nucleus accumbens core, with the caudate-putamen having the least. Neither dopamine D2 nor D3 agonists affected the uptake rates in nucleus accumbens but concentrations greater than 0.3 muM lowered the uptake rate in caudate-putamen. To validate our method of evaluating dopamine D2 and D3 autoreceptors, sulpiride (D2 antagonist) and nafadotride (D3 antagonist) were used to reverse the effects of the dopamine agonists to approximately 100% of the pre-agonist dopamine release concentration. Finally, these results demonstrate a functional voltammetric assay that characterizes dopamine D2-like agonist as either D2- or D3-preferring agonists by taking advantage of the unique receptor density within the striatum.

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A synaptomic analysis reveals dopamine hub synapses in the mouse striatum.

Publications

A synaptomic analysis reveals dopamine hub synapses in the mouse striatum.

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