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Cellular eyelashes help striatal neurons hook up

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Science Translational Medicine  23 Aug 2017:
Vol. 9, Issue 404, eaao4214
DOI: 10.1126/scitranslmed.aao4214


Primary cilia-based signaling provides critical infrastructure for formation of striatal neuronal networks.

Primary cilia (latin word for eyelashes) are micron-sized antenna-like organelles that extend from the cell body and serve as robust signaling hubs. Home to a diverse cast of receptors and ion channels, primary cilia help relay information from the cell’s local external environment to the cell body, and alas, ciliar dysfunctions are associated with cognitive impairments. Recent findings reveal that in neurons, primary cilia play a key role in establishing and maintaining the balance between excitatory and inhibitory inputs, sparking new hypotheses regarding mechanisms underlying neurodevelopmental disorders.

Guo et al. paved the way for understanding the role of primary cilia in neuronal development and integration focusing on the striatum, a region of the brain coordinating many aspects of cognition and brain function. Mouse genetics approaches enabled the deletion of the Arl13b gene that encodes a small guanosine triphosphatase (GTPase) important for ciliary function, specifically in inhibitory interneurons. This deletion led to morphological defects in interneurons including decreased dendritic and axonal complexity as well as reduced synaptic bouton density. The morphological changes resulted in impaired synaptic activity, revealing an overall excitatory/inhibitory imbalance. Moreover, Arl13b deletion was associated with decreased ciliar adenosine triphosphate (ATP)-induced calcium activity as well as decreased hotspots of calcium activity typical of these structures. In an elegant set of experiments, the authors were able to rescue the morphological and physiological features associated with Arl13b-deficiency by activating or overexpressing a ciliar G protein–coupled receptor. Finally, in contrast to normal human ARL13B, transduction of Arl13b-deficient interneurons with several ARL13B harboring mutations associated with Joubert syndrome, a neurodevelopmental disorder, failed to rescue signal transduction and interneuron connectivity. These data support a model in which signaling in primary cilia instructs the proper development and connectivity of striatal interneurons and provides a new platform for testing the role of ciliary signaling in the pathogenesis of neurodevelopmental disorders.

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