A Role for Dystonia-Associated Genes in Spinal GABAergic Interneuron Circuitry

Publication date: 17 October 2017
Source:Cell Reports, Volume 21, Issue 3
Author(s): Juliet Zhang, Jarret A.P. Weinrich, Jeffrey B. Russ, John D. Comer, Praveen K. Bommareddy, Richard J. DiCasoli, Christopher V.E. Wright, Yuqing Li, Peter J. van Roessel, Julia A. Kaltschmidt
Spinal interneurons are critical modulators of motor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. Although deficits in presynaptic inhibition have been inferred in human motor diseases, including dystonia, it remains unclear whether GABApre circuit components are altered in these conditions. Here, we use developmental timing to show that GABApre neurons are a late Ptf1a-expressing subclass and localize to the intermediate spinal cord. Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia-related protein Tor1a. Furthermore, in Tor1a mutant mice in which Klhl14 and Tor1a binding is disrupted, formation of GABApre sensory afferent synapses is impaired. Our findings suggest a potential contribution of GABApre neurons to the deficits in presynaptic inhibition observed in dystonia.

Graphical abstract

Teaser

GABApre spinal interneurons gate sensory inputs onto motor neurons. Zhang et al. localize GABApre neurons to the intermediate spinal cord and show that these interneurons express hereditary dystonia-related genes Klhl14 and Tor1a. In Tor1a mutant mice, GABApre synapse formation is disrupted, suggesting that spinal circuits may be affected in dystonia.


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