A ROLE FOR DYSTONIA-ASSOCIATED GENES IN SPINAL GABAERGIC INTERNEURON CIRCUITRY

Spinal interneurons are critical modulators of locomotor 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. While deficits in presynaptic inhibition have been inferred in human locomotor diseases, including dystonia, it remains unknown whether GABApre circuit components are altered in these conditions. In this study, 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 (Dyt1ΔE), GABApre-sensory afferent synapse formation is impaired. Our findings suggest a potential contribution of GABApre neurons to the deficits in presynaptic inhibition observed in dystonia. 9 total samples were analyzed: three replicates (1, 2, and 3) with samples from 3 regions of the spinal cord (D, I, and V) each.