Presynaptic inhibition of spinal sensory feedback ensures smooth movement
Open accessAbstract
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.
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The mid inhibitory cell types were grouped as one family comprising Inhib-15, Inhib-16, Inhib-17, Inhib-18, Inhib-19, Inhib-20, and Inhib-21, which expressed Slc6a5 (except Inhib-21) and Gad2, implicating these neurons in sensorimotor processing.
“The mid inhibitory cell types were grouped as one family comprised of Inhib-15, Inhib-16, Inhib-17, Inhib-18, Inhib-19, Inhib-20, and Inhib-21, which expressed the glycinergic marker Slc6a5 (with the exception of Inhib-21) and also the gaba-ergic marker Gad2, implicating these neurons in sensorimotor processing84–86.”
From A harmonized atlas of mouse spinal cord cell types and their spatial organization (2021) · cites this paper as [86]
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- Authors
- Fink, A. J. P., Croce, K. R., Huang, Z. J., Abbott, L. F., Jessell, T. M., & Azim, E.
- Affiliations
- Howard Hughes Medical Institute (US)
- Cold Spring Harbor Laboratory (US)
- Columbia University (US)
- Corresponding author
- Fink, Andrew J. P.
- Jessell, Thomas M.
- Venue
- Nature
- Published
- 2014-04-30
- Volume
- 509
- Issue
- 7498
- Pages
- 43-48
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4292914
- OpenAlex
- W2094208797
- Cited by
- 260
- References
- 56
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 32 · 2023: 25 · 2022: 25 · 2021: 29 · 2020: 25 · 2019: 19 · 2018: 19 · 2017: 15 · 2016: 19 · 2015: 18 · 2014: 5
- FWCI
- 10.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (MH093338, MH078844, U01MH078844, R01MH093338)
- National Institute of Neurological Disorders and Stroke (R01NS080932, NS033245, R37NS033245, R01NS033245)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007430)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Motor Control and Adaptation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- presynaptic inhibition, GAD-2, axo-axonic synapses, sensory feedback, proprioceptive afferents, gain control, movement smoothness
- MeSH terms
- Animals, Axons, Efferent Pathways, Female, Forelimb, Glutamate Decarboxylase, Interneurons, Male, Models, Neurological, Motor Skills, Movement, Neural Inhibition, Spinal Cord, Presynaptic Terminals, Neurotransmitter Agents, Mice, Feedback, Sensory, GABAergic Neurons
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