EphA4-Mediated Ipsilateral Corticospinal Tract Misprojections Are Necessary for Bilateral Voluntary Movements But Not Bilateral Stereotypic Locomotion

Abstract

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.

Skilled Movements Require Non-apoptotic Bax/Bak Pathway-Mediated Corticospinal Circuit Reorganization

“…Electrical responses were recorded from various muscle pairs (Bi/Tri, Ecr/Fcr, and Fcu/Fcr) using percutaneous Ni-chrome wire electrodes (deinsulated 1 mm from the tip) in response to motor cortex threshold stimulation as previously reported (Serradj et al, 2014). EMG recording wires were inserted using a 27-gauge hypodermic needle guide.…”

Activity-Based Therapies for Repair of the Corticospinal System Injured during Development

“…Modified from Serradj et al (17). (A) CST terminations within the intermediate zone flanking the midline.…”

Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome

“…α2-Chimaerin is reported to act downstream of several receptors implicated in axon growth and guidance, including EPH receptor A4 (EphA4), TrkB, and neu-mice to Isl MN -GFP reporter mice -an allele of the ISL1 transcripropilin 1/plexinA (11)(12)(13)(14)(15)(16)18). Epha4 KO/KO and Chn1 KO/KO adult mice have a rabbit-like hopping gait, resulting from aberrant re-crossing of the corticospinal tract and miswiring of spinal interneurons that regulate central pattern generator (CPG) circuitry within the spinal cord (12,14,15,(19)(20)(21)(22). α2-Chimaerin, furthermore, has been shown to interact with phosphorylated residues on EphA4 to alter cytoskeletal dynamics and elicit growth cone collapse (12,13,15).…”