Spinal glutamatergic neurons defined by EphA4 signaling are essential components of normal locomotor circuits

Lotta Borgius; Hiroshi Nishimaru; Vanessa Caldeira; Yuka Kunugise; Peter Löw; Ramon Reig; Shigeyoshi Itohara; Takuji Iwasato; Ole Kiehn

doi:10.1523/jneurosci.4992-13.2014

Spinal glutamatergic neurons defined by EphA4 signaling are essential components of normal locomotor circuits

Lotta Borgius, Hiroshi Nishimaru, Vanessa Caldeira, Yuka Kunugise, Peter Löw, Ramon Reig, Shigeyoshi Itohara, Takuji Iwasato, Ole Kiehn^*

^*Corresponding author for this work

32 Citations (Scopus)

Abstract

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. Here, using intersectional genetics, we demonstrate that a spinal cord-specific deletion of EphA4 signaling is sufficient to generate the overground hopping gait. In contrast, selective deletion of EphA4 signaling in forebrain neurons, including the corticospinal tract neurons, did not result in a change in locomotor pattern. The gait switch was attributed to the loss of EphA4 signaling in excitatory Vglut2⁺ neurons, which is accompanied by an increased midline crossing of Vglut2⁺ neurons in the ventral spinal cord. Our findings functionally define spinal EphA4 signaling in excitatory Vglut2⁺ neurons as required for proper organization of the spinal locomotor circuitry, and place these cells as essential components of the mammalian locomotor network.

Original language	English
Journal	Journal of Neuroscience
Volume	34
Issue number	11
Pages (from-to)	3841-3853
Number of pages	13
ISSN	0270-6474
DOIs	https://doi.org/10.1523/jneurosci.4992-13.2014
Publication status	Published - 1 Jan 2014
Externally published	Yes

Keywords

Central pattern generator
EphA4
Locomotion
Spinal cord
α-chimaerin

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abstract = "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. Here, using intersectional genetics, we demonstrate that a spinal cord-specific deletion of EphA4 signaling is sufficient to generate the overground hopping gait. In contrast, selective deletion of EphA4 signaling in forebrain neurons, including the corticospinal tract neurons, did not result in a change in locomotor pattern. The gait switch was attributed to the loss of EphA4 signaling in excitatory Vglut2+ neurons, which is accompanied by an increased midline crossing of Vglut2+ neurons in the ventral spinal cord. Our findings functionally define spinal EphA4 signaling in excitatory Vglut2+ neurons as required for proper organization of the spinal locomotor circuitry, and place these cells as essential components of the mammalian locomotor network.",

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AU - Caldeira, Vanessa

AU - Kunugise, Yuka

AU - Löw, Peter

AU - Reig, Ramon

AU - Itohara, Shigeyoshi

AU - Iwasato, Takuji

AU - Kiehn, Ole

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N2 - 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. Here, using intersectional genetics, we demonstrate that a spinal cord-specific deletion of EphA4 signaling is sufficient to generate the overground hopping gait. In contrast, selective deletion of EphA4 signaling in forebrain neurons, including the corticospinal tract neurons, did not result in a change in locomotor pattern. The gait switch was attributed to the loss of EphA4 signaling in excitatory Vglut2+ neurons, which is accompanied by an increased midline crossing of Vglut2+ neurons in the ventral spinal cord. Our findings functionally define spinal EphA4 signaling in excitatory Vglut2+ neurons as required for proper organization of the spinal locomotor circuitry, and place these cells as essential components of the mammalian locomotor network.

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Spinal glutamatergic neurons defined by EphA4 signaling are essential components of normal locomotor circuits

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