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    Modelling genetic reorganization in the mouse spinal cord affecting left-right coordination during locomotion.
    J Physiol 2013 Nov 30;591(22):5491-508. Epub 2013 Sep 30.
    I. A. Rybak: Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
    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.

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    Spinal glutamatergic neurons defined by EphA4 signaling are essential components of normal locomotor circuits.
    J Neurosci 2014 Mar;34(11):3841-53
    Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm, Sweden, Faculty of Medicine and College of Biological Sciences, University of Tsukuba, 305-8577 Tsukuba, Japan, RIKEN Brain Science Institute, 351-0198 Wako, Japan, and National Institute of Genetics, SOKENDAI, 411-8540 Mishima, Japan.
    EphA4 signaling is essential for the spatiotemporal organization of neuronal circuit formation. In mice, deletion of this signaling pathway causes aberrant midline crossing of axons from both brain and spinal neurons and the complete knock-outs (KOs) exhibit a pronounced change in motor behavior, where alternating gaits are replaced by a rabbit-like hopping gait. The neuronal mechanism that is responsible for the gait switch in these KO mice is not known. Read More
    Change in the balance of excitatory and inhibitory midline fiber crossing as an explanation for the hopping phenotype in EphA4 knockout mice.
    Eur J Neurosci 2011 Oct 7;34(7):1102-12. Epub 2011 Sep 7.
    Mammalian Locomotor Laboratory, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm, Sweden.
    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. Read More
    Organization of left-right coordination of neuronal activity in the mammalian spinal cord: Insights from computational modelling.
    J Physiol 2015 Jun;593(11):2403-26
    Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
    Key Points: Coordination of neuronal activity between left and right sides of the mammalian spinal cord is provided by several sets of commissural interneurons (CINs) whose axons cross the midline. Genetically identified inhibitory V0D and excitatory V0V CINs and ipsilaterally projecting excitatory V2a interneurons were shown to secure left-right alternation at different locomotor speeds. We have developed computational models of neuronal circuits in the spinal cord that include left and right rhythm-generating centres interacting bilaterally via three parallel pathways mediated by V0D , V2a-V0V and V3 neuron populations. Read More
    Dorsally derived spinal interneurons in locomotor circuits.
    Ann N Y Acad Sci 2013 Mar;1279:32-42
    Unit of Developmental Genetics, Science for Life Laboratory, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    During neuronal circuit formation, axons are guided to their targets by the help of axon guidance molecules, which are required for establishing functional circuits. A promising system to dissect the development and functionalities of neuronal circuitry is the spinal cord central pattern generator (CPG) for locomotion, which converts a tonic supraspinal drive to rhythmic and coordinated movements. Here we describe concepts arising from genetic studies of the locomotor network with a focus on the position and roles of commissural interneurons. Read More