Abstract
SUMMARYMidbrain dopaminergic (mDA) neurons exhibit extensive dendritic and axonal arborizations, but local protein synthesis is not characterized in these neurons. Here, we investigate messenger RNA (mRNA) localization and translation in mDA neuronal axons and dendrites, both of which release dopamine (DA). Using highly sensitive ribosome-bound RNA sequencing and imaging approaches, we find no evidence for mRNA translation in mDA axons. In contrast, mDA neuronal dendrites in the substantia nigra pars reticulata (SNr) contain ribosomes and mRNAs encoding the major components of DA synthesis, release, and reuptake machinery. Surprisingly, we also observe dendritic localization of mRNAs encoding synaptic vesicle-related proteins, including those involved in exocytic fusion. Our results are consistent with a role for local translation in the regulation of DA release from dendrites, but not from axons. Our translatome data define a molecular signature of sparse mDA neurons in the SNr, including the enrichment of Atp2a3/SERCA3, an atypical ER calcium pump.
Highlights
Midbrain dopaminergic neurons play critical roles in reward processing, movement control, and cognitive function
We removed all tissue medial to the lateral ventricles in our striatal dissections of DATIRESÀCre/wt;RiboTag+/– mice to ensure that striatal eL22-HA was derived from solely from Midbrain dopaminergic (mDA) axons
The yield and enrichment of Th messenger RNA (mRNA) were significantly higher in our 1% ventral midbrain (VM) spike-in controls than striatal IPs from CreÀ and Cre+ mice (Figures 2E and 2F). These results demonstrate sensitive, quantitative RiboTag IP from distinct mDA neuron compartments and suggest that Th and Slc6a3/DA transporter (DAT) mRNAs are translated in dopaminergic dendrites in the substantia nigra pars reticulata (SNr), but not in striatal mDA axons (Table 1)
Summary
Midbrain dopaminergic (mDA) neurons play critical roles in reward processing, movement control, and cognitive function. Their elaborate cytoarchitecture includes unmyelinated axons that course through the medial forebrain bundle (MFB) to reach basal ganglia and cortical targets (Bjorklund and Dunnett, 2007). In addition to axonal DA release in the striatum and cortex, mDA neurons release DA within the midbrain (reviewed in Rice and Patel, 2015 and Cheramy et al, 1981), including from ventrally directed dendrites of SNc neurons that can project more than 500 mm into the substantia nigra pars reticulata (SNr) (Geffen et al, 1976; Korf et al, 1976; Tepper et al, 1987).
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