Change in the balance of excitatory and inhibitory midline fiber crossing as an explanation for the hopping phenotype in EphA4 knockout mice.

Neuronal networks in the spinal cord termed central pattern generators (CPGs) are responsible for the generation of rhythmic movements, such as walking. The axon guidance molecule EphA4 has been suggested to play a role in the configuration of spinal CPG networks in mammals. In EphA4 knockout (EphA4-KO) mice, the normal alternating walking pattern is replaced by a rabbit-like hopping gait, which can be reproduced when locomotor-like activity is induced in the isolated spinal cord.

Transmitter-phenotypes of commissural interneurons in the lumbar spinal cord of newborn mice.

Commissural interneurons (CINs) are a necessary component of central pattern generators (CPGs) for locomotion because they mediate the coordination of left and right muscle activity. The projection patterns and relative locations of different classes of CINs in the ventromedial part of the rodent lumbar cord have been described (Eide et al. [1999] J Comp Neurol 403:332-345; Stokke et al.

Genetic ablation of V2a ipsilateral interneurons disrupts left-right locomotor coordination in mammalian spinal cord.

The initiation and coordination of activity in limb muscles are the main functions of neural circuits that control locomotion. Commissural neurons connect locomotor circuits on the two sides of the spinal cord, and represent the known neural substrate for left-right coordination. Here we demonstrate that a group of ipsilateral interneurons, V2a interneurons, plays an essential role in the control of left-right alternation.

Phenotype of V2-derived interneurons and their relationship to the axon guidance molecule EphA4 in the developing mouse spinal cord.

The ventral spinal cord consists of interneuron groups arising from distinct, genetically defined, progenitor domains along the dorsoventral axis. Many of these interneuron groups settle in the ventral spinal cord which, in mammals, contains the central pattern generator for locomotion. In order to better understand the locomotor networks, we have used different transgenic mice for anatomical characterization of one of these interneuron groups, called V2 interneurons.

Excitatory components of the mammalian locomotor CPG.

Locomotion in mammals is to a large degree controlled directly by intrinsic spinal networks, called central pattern generators (CPGs). The overall function of these networks is governed by interaction between inhibitory and excitatory neurons. In the present review, we will discuss recent findings addressing the role of excitatory synaptic transmission for network function including the role of specific excitatory neuronal populations in coordinating muscle activity and in generating rhythmic activity.

EphA4 defines a class of excitatory locomotor-related interneurons.

Relatively little is known about the interneurons that constitute the mammalian locomotor central pattern generator and how they interact to produce behavior. A potential avenue of research is to identify genetic markers specific to interneuron populations that will assist further exploration of the role of these cells in the network. One such marker is the EphA4 axon guidance receptor.

ShcA regulates neurite outgrowth stimulated by neural cell adhesion molecule but not by fibroblast growth factor 2: evidence for a distinct fibroblast growth factor receptor response to neural cell adhesion molecule activation.

Homophilic binding in trans of the neural cell adhesion molecule (NCAM) mediates adhesion between cells and leads, via activation of intracellular signaling cascades, to neurite outgrowth in primary neurons as well as in the neuronal cell line PC12. NCAM mediates neurite extension in PC12 cells by two principal routes of signaling: NCAM/Fyn and NCAM/fibroblast growth factor receptor (FGFR), respectively. Previous studies have shown that activation of mitogen-activated protein kinases is a pivotal point of convergence in NCAM signaling, but the mechanisms behind this activation are not clear.

Role of EphA4 and EphrinB3 in local neuronal circuits that control walking.

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.