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

Zhang J, Weinrich JAP, Russ JB, Comer JD, Bommareddy PK, DiCasoli RJ, Wright CVE, Li Y, van Roessel PJ, Kaltschmidt JA
Cell Rep. 2017 21 (3): 666-678

PMID: 29045835 · PMCID: PMC5658202 · DOI:10.1016/j.celrep.2017.09.079

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.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (15)

Animals Biomarkers Dystonia GABAergic Neurons Genetic Predisposition to Disease Interneurons Male Mice, Mutant Strains Molecular Chaperones Mutation Nerve Net Presynaptic Terminals Proprioception Spinal Cord Transcription Factors

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