Role of EphA4 and EphrinB3 in Local Neuronal Circuits That Control Walking

Abstract

Local circuits in the spinal cord that generate locomotion are termed central pattern generators (CPGs). These provide coordinated bilateral control over the normal limb alternation that underlies walking. The molecules that organize the mammalian CPG are unknown. Isolated spinal cords from mice lacking either the EphA4 receptor or its ligand ephrinB3 have lost left-right limb alternation and instead exhibit synchrony. We identified EphA4-positive neurons as an excitatory component of the locomotor CPG. Our study shows that dramatic locomotor changes can occur as a consequence of local genetic rewiring and identifies genes required for the development of normal locomotor behavior.

EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line

“…Although, in this article, EphA4 was not discussed in association with ephrin-B3, there are some previous reports about the interaction between ephrin-B3 and EphA4 (38,39). In summary, these studies provide the evidence that EphrinB3/EphA4 has an important role in neuronal circuit formation, growth, and development.…”

EphA4 defines a class of excitatory locomotor-related interneurons

“…Previously, we have shown that the abnormal adult hopping gait in ephA4-KO mice can be elicited in the isolated neonatal spinal cord preparation, suggesting that intrinsic defects in the spinal cord locomotor CPG underlie this phenotype (16). In the isolated spinal cord, the abnormal hopping gait was seen as synchrony between bilaterally located, lumbar segment 2 (L2) predominantly flexor motor neurons as well as synchrony between caudally located, predominantly extensor L5 motor neurons.…”

“…1C), because the iL2 ventral root activity always showed strict alternation with that of the iL5 in all preparations (WT, heterozygote, and homozygote; also see ref. 16). …”

“…A recent example of a genetic loss-of-function that is related to a distinct abnormal behavioral phenotype is the rabbit-like hopping gait exhibited in mice that have a targeted deletion of the axon guidance molecules EphA4 and ephrinB3 (13)(14)(15). This pronounced phenotype could be reproduced in isolated spinal cords from mutant mice, suggesting that the neuronal network controlling locomotion, also called the central pattern generator (CPG), is genetically reconfigured in the mutants (16). The experiments demonstrated that the hopping gait in mutants was related to an increase in midline crossing of axons originating from EphA4-expressing neurons in the spinal cord.…”

Selective Manipulation of Neural Circuits

“…Selective expression of a genetic tool in the glutamatergic neurons in hindbrain and spinal cord has been achieved by inserting a transgene under the control of vesicular glutamate transporter 2 (Vglut2) promoter [18]. Vglut2 is the dominant glutamate transporter expressed by in these regions [22,23]. In this transgenic mouse, the genetic tool was found only in Vglut2-positive neurons in the central nervous system and exclusively activated by photostimulation.…”