Smooth Move: How GABAergic Interneurons Regulate Skilled Motor Behavior

November 16, 2014March 5, 2017 Jillian L. Shaw Afferent Sensory Neurons, Alex Honnold, Efferent Motor Neurons, GABA, GABAergic neurons, GAD2, inhibitory, Interneuron, Microcircuit, motor neuron, Nature, Oscillation, Presynaptic inhibition, Proprioception, SfN14, Spinal cord, Thomas Jessel

In early 2014, the American free-solo rock climber Alex Honnold climbed 2,500 feet of limestone without ropes. The demanding route called El Sendero Luminoso in El Potrero Chico, Mexico required 3 hours of intense concentration and precise movements. One wrong move and the young climber would have fallen thousands of feet with catastrophic consequences. In the video featured below, you see Honnold’s skilled movements and elegant displays of strength and precision. His ability to dramatically support his body weight with his fingertips and scale the wall like a spider monkey is due to the elaborate neural transformations that are directing each motor act. The ability to perform an action like a climb is dependent on sensory feedback and refinement of local inhibitory microcircuits. Goal-directed reaching behavior depends on a hardwired control systems that underlies our capacity to smoothly execute movement.

[youtube=https://www.youtube.com/watch?v=Phl82D57P58]

In an exciting paper in Nature, Dr. Thomas Jessel (a scientist featured this week at the Society for Neuroscience meeting in Washington, D.C. See his talk entitled “Circuits and Strategies for Skilled Motor Behavior” on Sunday November 16, 2014 from 2:30-3:40PM.) and his colleagues explored how GABAergic interneurons exert presynaptic inhibitory control over sensory-motor transmission.

The spinal cord receives sensory inputs from the periphery through the afferent sensory neurons. The nerve impulses from the spinal cord are, in turn, carried towards effectors like muscles through the efferent motor neurons. The motor neurons in the spinal cord receive a constant barrage of excitatory inputs. Motor outputs as simple as walking or as complex as rock climbing are dependent on the capacity for interneurons to inhibit and properly shape the response to this excitation. Most interneurons of the inhibitory variety form direct connections with motor neurons. The big discovery of this paper is the finding that a small subset of these GABAergic interneurons form contact with the sensory afferent terminals that regulate sensory-motor interactions and regulate this process through presynaptic inhibition (see Figure below).

Left: It was previously known that inhibitory interneurons (light green) form contacts with motor neurons (deep blue) in the spinal cord. In the latest paper from Dr. Jessel's group, it was discovered that a subset of interneurons (orange) also form contacts with the sensory afferent terminals (green and light blue), further regulating coordinated movements. Right: Both excitatory (vGlut1) and inhibitory (GAD) contacts at the motor neuron modulate its firing. — Left: It was previously known that inhibitory interneurons (light green) form contacts with motor neurons (deep blue) in the spinal cord. In the latest paper from Dr. Jessel’s group, it was discovered that a subset of interneurons (orange) also form contacts with the sensory afferent terminals (green and light blue), further regulating coordinated movements. Right: Both excitatory (vGlut1) and inhibitory (GAD) contacts at the motor neuron modulate its firing.

One thing that differentiates the inhibitory interneurons that form this axo-axonic connection with the sensory synapse from other spinal inhibitory neurons is the expression of GAD2. GAD2 is a GABA-synthesizing enzyme. The researchers manipulated GAD2 expression to determine whether they could perturb motor behavior as a result. One thing to understand about the model of how sensory-motor control influences execution of coordinated movement is that gaining proprioceptive feedback causes motor oscillations or alternating joint extensions. The interpretation here is that if you eliminate presynaptic inhibition then you can disrupt proprioceptive feedback driven oscillations that lead to motor problems.

This paper contributes greatly to our understanding of the link between presynaptic inhibitory control and how eliminating this inhibition negatively influences motor behaviors. The authors were able to activate and then eliminate the spinal GABAergic interneurons specifically responsible for presynaptic inhibition at sensory synapses. These neurons are crucial for suppressing motor oscillations during motor movement – when these neurons are inactivated, the oscillation disappears. At the circuit level, climbers like Honnold have GABA pre-synaptic neurons to thank for controlling task-appropriate smooth movements up the rock.

References:

Fink A.J.P., Z. Josh Huang, L. F. Abbott, Thomas M. Jessell & Eiman Azim (2014). Presynaptic inhibition of spinal sensory feedback ensures smooth movement, Nature, 509 (7498) 43-48. DOI: http://dx.doi.org/10.1038/nature13276

Image made by Jooyeun Lee.

Author

Jillian L. Shaw

Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College. After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year. A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience. Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration. When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.