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

TY - JOUR

T1 - Change in the balance of excitatory and inhibitory midline fiber crossing as an explanation for the hopping phenotype in EphA4 knockout mice

AU - Restrepo, Carlos E.

AU - Margaryan, Gayane

AU - Borgius, Lotta

AU - Lundfald, Line

AU - Sargsyan, Davit

AU - Kiehn, Ole

PY - 2011/10/1

Y1 - 2011/10/1

N2 - 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. This hopping phenotype has been explained by an abnormal midline crossing of ipsilateral axons. Here, we investigated the nature of this overcrossing in heterozygous EphA4 (EphA4 lacZ/+) mice that showed normal alternating gait and homozygous EphA4 (EphA4 lacZ/lacZ) mice with hopping gait. Localized lesions showed that the hopping phenotype is maintained by fibers crossing in the ventral commissure. Using transgenic mouse lines in which glutamatergic, GABAergic and glycinergic neurons are intrinsically labeled, we showed a significant increase in the number of crossing excitatory β-galactosidase-positive neurons and a decrease in the number of inhibitory neurons crossing the midline in EphA4 lacZ/lacZ mice compared with EphA4 lacZ/+ mice. These results show that the hopping phenotype is the result of a change in the balance between excitatory and inhibitory signals across the midline and that EphA4-positive neurons play an essential role in the mammalian CPG.

AB - 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. This hopping phenotype has been explained by an abnormal midline crossing of ipsilateral axons. Here, we investigated the nature of this overcrossing in heterozygous EphA4 (EphA4 lacZ/+) mice that showed normal alternating gait and homozygous EphA4 (EphA4 lacZ/lacZ) mice with hopping gait. Localized lesions showed that the hopping phenotype is maintained by fibers crossing in the ventral commissure. Using transgenic mouse lines in which glutamatergic, GABAergic and glycinergic neurons are intrinsically labeled, we showed a significant increase in the number of crossing excitatory β-galactosidase-positive neurons and a decrease in the number of inhibitory neurons crossing the midline in EphA4 lacZ/lacZ mice compared with EphA4 lacZ/+ mice. These results show that the hopping phenotype is the result of a change in the balance between excitatory and inhibitory signals across the midline and that EphA4-positive neurons play an essential role in the mammalian CPG.

KW - Central pattern generator

KW - Locomotion

KW - Motor neurons

KW - Spinal cord

UR - http://www.scopus.com/inward/record.url?scp=80053576960&partnerID=8YFLogxK

U2 - 10.1111/j.1460-9568.2011.07838.x

DO - 10.1111/j.1460-9568.2011.07838.x

M3 - Journal article

C2 - 21899605

AN - SCOPUS:80053576960

SN - 0953-816X

VL - 34

SP - 1102

EP - 1112

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

IS - 7

ER -