Presynaptic inhibition of spinal sensory feedback ensures smooth movement

The precision of skilled movement depends on sensory feedback and its refinement by local inhibitory microcircuits. One specialized set of spinal GABAergic interneurons forms axo–axonic contacts with the central terminals of sensory afferents, exerting presynaptic inhibitory control over sensory–motor transmission. The inability to achieve selective access to the GABAergic neurons responsible for this unorthodox inhibitory mechanism has left unresolved the contribution of presynaptic inhibition to motor behaviour. We used Gad2 as a genetic entry point to manipulate the interneurons that contact sensory terminals, and show that activation of these interneurons in mice elicits the defining physiological characteristics of presynaptic inhibition. Selective genetic ablation of Gad2 -expressing interneurons severely perturbs goal-directed reaching movements, uncovering a pronounced and stereotypic forelimb motor oscillation, the core features of which are captured by modelling the consequences of sensory feedback at high gain. Our findings define the neural substrate of a genetically hardwired gain control system crucial for the smooth execution of movement. A population of spinal interneurons that form axo–axonic connections with the terminals of proprioceptive afferents are shown to mediate presynaptic inhibition; their ablation elicits harmonic oscillations during goal-directed forelimb movements, which can be modelled as the consequence of an increase in sensory feedback gain. How presynaptic inhibition ensures smooth limb movement Humans and other animals execute limb movements with a seemingly effortless precision that relies on sensory feedback and its refinement by inhibitory microcircuits. A new study identifies presynaptic inhibition in the spinal cord, a regulatory filter mediated by Gad2 -expressing GABAergic interneurons that form connections with the terminals of sensory afferents, as part of a hardwired gain control system crucial for the smooth execution of movement. Thomas Jessell and colleagues demonstrate that activation of Gad2 -expressing neurons inhibits neurotransmitter release from sensory afferents. Selective ablation of these neurons in mice causes pronounced oscillations during goal-directed forelimb reaching movements, a behaviour captured by a model of sensory feedback at high gain.