EphA4-mediated ipsilateral corticospinal tract misprojections are necessary for bilateral voluntary movements but not bilateral stereotypic locomotion.
In this study, we took advantage of the reported role of EphA4 in determining the contralateral spinal projection of the corticospinal tract (CST) to investigate the effects of ipsilateral misprojections on voluntary movements and stereotypic locomotion. Null EphA4 mutations produce robust ipsilateral CST misprojections, resulting in bilateral corticospinal tracts. We hypothesize that a unilateral voluntary limb movement, not a stereotypic locomotor movement, will become a bilateral movement in EphA4 knock-out mice with a bilateral CST. However, in EphA4 full knock-outs, spinal interneurons also develop bilateral misprojections. Aberrant bilateral spinal circuits could thus transform unilateral corticospinal control signals into bilateral movements. We therefore studied mice with conditional forebrain deletion of the EphA4 gene under control by Emx1, a gene expressed in the forebrain that affects the developing CST but spares brainstem motor pathways and spinal motor circuits. We examined two conditional knock-outs targeting forebrain EphA4 during performance of stereotypic locomotion and voluntary movement: adaptive locomotion over obstacles and exploratory reaching. We found that the conditional knock-outs used alternate stepping, not hopping, during overground locomotion, suggesting normal central pattern generator function and supporting our hypothesis of minimal CST involvement in the moment-to-moment control of stereotypic locomotion. In contrast, the conditional knock-outs showed bilateral voluntary movements under conditions when single limb movements are normally produced and, as a basis for this aberrant control, developed a bilateral motor map in motor cortex that is driven by the aberrant ipsilateral CST misprojections. Therefore, a specific change in CST connectivity is associated with and explains a change in voluntary movement.
Department of Physiology, Pharmacology and Neuroscience, City College of the City University of New York, New York, New York 10031; Department of Molecules-Signaling-Development, Max Planck Institute of Neurobiology, D-82152 Martinsried, Germany, Munich Cluster for Systems Neurology (SyNergy), D-80336 Munich, Germany; and Department of Neuroscience, Science for Life Laboratory, University of Uppsala, 75124 Uppsala, Sweden.
Najet
N
Serradj
Sónia
S
Paixão
Tomasz
T
Sobocki
Mitchell
M
Feinberg
Rüdiger
R
Klein
Klas
K
Kullander
John H
JH
Martin
D000818:Animals; D063226:Central Pattern Generators / Q000378:metabolism / Q000502:physiology; D005106:Exploratory Behavior; D017353:Gene Deletion; D007395:Interneurons / Q000378:metabolism / Q000502:physiology; D008124:Locomotion; D051379:Mice; D008810:Mice, Inbred C57BL; D009044:Motor Cortex / Q000502:physiology; D011712:Pyramidal Tracts / Q000378:metabolism / Q000502:physiology*; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*
D036122:Receptor, EphA4
EphA4; corticospinal tract; locomotion; motor cortex; reaching