TY - JOUR
T1 - Modelling genetic reorganization in the mouse spinal cord affecting left-right coordination during locomotion
AU - Rybak, Ilya A.
AU - Shevtsova, Natalia A.
AU - Kiehn, Ole
PY - 2013/11/1
Y1 - 2013/11/1
N2 - Abstract The spinal neural circuit contains inhibitory (CINi) and excitatory (CINe) commissural interneurons with axons crossing the mid-line. Direction of these axons to the other side of the cord is controlled by axon guidance molecules, such as Netrin-1 and DCC. The cord also contains glutamatergic interneurons, whose axon guidance involves the EphA4 receptor. In EphA4 knockout (KO) and Netrin-1 KO mice, the normal left-right alternating pattern is replaced with a synchronized hopping gait, and the cord of DCC KO mice exhibits uncoordinated left and right oscillations. To investigate the effects of these genetic transformations, we used a computational model of the spinal circuits containing left and right rhythm-generating neuron populations (RGs), each with a subpopulation of EphA4-positive neurons, and CINi and CINe populations mediating mutual inhibition and excitation between the left and right RGs. In the EphA4 KO circuits, half of the EphA4-positive axons crossed the mid-line and excited the contralateral RG neurons. In the Netrin-1 KO model, the number of contralateral CINi projections was significantly reduced, while in the DCC KO model, the numbers of both CINi and CINe connections were reduced. In our simulations, the EphA4 and Netrin-1 KO circuits switched from the left-right alternating pattern to a synchronized hopping pattern, and the DCC KO network exhibited uncoordinated left-right activity. The amplification of inhibitory interactions re-established an alternating pattern in the EphA4 and DCC KO circuits, but not in the Netrin-1 KO network. The model reproduces the genetic transformations and provides insights into the organization of the spinal locomotor network.
AB - Abstract The spinal neural circuit contains inhibitory (CINi) and excitatory (CINe) commissural interneurons with axons crossing the mid-line. Direction of these axons to the other side of the cord is controlled by axon guidance molecules, such as Netrin-1 and DCC. The cord also contains glutamatergic interneurons, whose axon guidance involves the EphA4 receptor. In EphA4 knockout (KO) and Netrin-1 KO mice, the normal left-right alternating pattern is replaced with a synchronized hopping gait, and the cord of DCC KO mice exhibits uncoordinated left and right oscillations. To investigate the effects of these genetic transformations, we used a computational model of the spinal circuits containing left and right rhythm-generating neuron populations (RGs), each with a subpopulation of EphA4-positive neurons, and CINi and CINe populations mediating mutual inhibition and excitation between the left and right RGs. In the EphA4 KO circuits, half of the EphA4-positive axons crossed the mid-line and excited the contralateral RG neurons. In the Netrin-1 KO model, the number of contralateral CINi projections was significantly reduced, while in the DCC KO model, the numbers of both CINi and CINe connections were reduced. In our simulations, the EphA4 and Netrin-1 KO circuits switched from the left-right alternating pattern to a synchronized hopping pattern, and the DCC KO network exhibited uncoordinated left-right activity. The amplification of inhibitory interactions re-established an alternating pattern in the EphA4 and DCC KO circuits, but not in the Netrin-1 KO network. The model reproduces the genetic transformations and provides insights into the organization of the spinal locomotor network.
UR - http://www.scopus.com/inward/record.url?scp=84887615519&partnerID=8YFLogxK
U2 - 10.1113/jphysiol.2013.261115
DO - 10.1113/jphysiol.2013.261115
M3 - Journal article
C2 - 24081162
AN - SCOPUS:84887615519
SN - 0022-3751
VL - 591
SP - 5491
EP - 5508
JO - Journal of Physiology
JF - Journal of Physiology
IS - 22
ER -