Disruption of Dopamine Receptor 1 Localization to Primary Cilia Impairs Signaling in Striatal Neurons

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 hypothe-sized 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 (D-1) in male and female mice, either by loss of a BBS protein or loss of the cilium itself, specifically in D-1-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 D-1-expressing neurons leads to a reduction in D-1-mediated signaling. Together, these results indicate that cilia impact D-1 activity in the nervous system and underscore the importance of neuronal cilia for proper GPCR signaling.