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Disruption of dopamine receptor 1 localization to primary cilia impairs signaling in striatal neurons
Journal article   Open access   Peer reviewed

Disruption of dopamine receptor 1 localization to primary cilia impairs signaling in striatal neurons

Toneisha Stubbs, Andrew Koemeter-Cox, James I Bingman, Fangli Zhao, Anuradha Kalyanasundaram, Leslie A Rowland, Muthu Periasamy, Calvin S Carter, Val C Sheffield, Candice C Askwith, …
The journal of neuroscience : the official journal of the Society for Neuroscience, Vol.42(35), pp.6692-6705
07/25/2022
DOI: 10.1523/JNEUROSCI.0497-22.2022
PMCID: PMC9436016
PMID: 35882560
url
https://doi.org/10.1523/JNEUROSCI.0497-22.2022View
Published (Version of record) Open Access

Abstract

A rod-shaped appendage called a primary cilium projects from the soma of most central neurons in the mammalian brain. The importance of cilia within the nervous system is highlighted by the fact that human syndromes linked to primary cilia dysfunction, collectively termed ciliopathies, are associated with numerous neuropathologies, including hyperphagia-induced obesity, neuropsychiatric disorders, and learning and memory deficits. Neuronal cilia are enriched with signaling molecules, including specific G-protein-coupled receptors (GPCRs) and their downstream effectors, suggesting that they act as sensory organelles that respond to neuromodulators in the extracellular space. We previously showed that GPCR ciliary localization is disrupted in neurons from mouse models of the ciliopathy Bardet-Biedl syndrome (BBS). Based on this finding, we hypothesized that mislocalization of ciliary GPCRs may impact receptor signaling and contribute to the BBS phenotypes. Here, we show that disrupting localization of the ciliary GPCR dopamine receptor 1 (D1) in male and female mice, either by loss of a BBS protein or loss of the cilium itself, specifically in D1-expressing neurons, results in obesity. Interestingly, the weight gain is associated with reduced locomotor activity, rather than increased food intake. Moreover, the loss of a BBS protein or cilia on D1-expressing neurons leads to a reduction in D1-mediated signaling. Together, these results indicate that cilia impact D1 activity in the nervous system and underscore the importance of neuronal cilia for proper GPCR signaling.

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