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Renshaw cells (V1 R ) are excitable as soon as they reach their final location next to the spinal motoneurons and are functionally heterogeneous. Using multiple experimental approaches, in combination with biophysical modeling and dynamical systems theory, we analyzed, for the first time, the mechanisms underlying the electrophysiological properties of V1 R during early embryonic development of the mouse spinal cord locomotor networks (E11.5-E16.5). We found that these interneurons are subdivided into several functional clusters from E11.5 and then display an unexpected transitory involution process during which they lose their ability to sustain tonic firing. We demonstrated that the essential factor controlling the diversity of the discharge pattern of embryonic V1 R is the ratio of a persistent sodium conductance to a delayed rectifier potassium conductance. Taken together, our results reveal how a simple mechanism, based on the synergy of two voltage-dependent conductances that are ubiquitous in neurons, can produce functional diversity in embryonic V1 R and control their early developmental trajectory., Competing Interests: JB, CM, HL, PB, YT, FL, CM, HA, JM, PL, AC No competing interests declared, (© 2021, Boeri et al.)

Spontaneous network activity (SNA) emerges in the spinal cord (SC) before the formation of peripheral sensory inputs and central descending inputs. SNA is characterized by recurrent giant depolarizing potentials (GDPs). Because GDPs in motoneurons (MNs) are mainly evoked by prolonged release of GABA, they likely necessitate sustained firing of interneurons. To address this issue we analyzed, as a model, embryonic Renshaw cell (V1 R ) activity at the onset of SNA (E12.5) in the embryonic mouse SC (both sexes). V1 R are one of the interneurons known to contact MNs, which are generated early in the embryonic SC. Here, we show that V1 R already produce GABA in E12.5 embryo, and that V1 R make synaptic-like contacts with MNs and have putative extrasynaptic release sites, while paracrine release of GABA occurs at this developmental stage. In addition, we discovered that V1 R are spontaneously active during SNA and can already generate several intrinsic activity patterns including repetitive-spiking and sodium-dependent plateau potential that rely on the presence of persistent sodium currents ( I Nap ). This is the first demonstration that I Nap is present in the embryonic SC and that this current can control intrinsic activation properties of newborn interneurons in the SC of mammalian embryos. Finally, we found that 5 μm riluzole, which is known to block I NaP ) are GABAergic at E12.5 and spontaneously active during SNA. We uncover a new role for persistent sodium currents ( I NaP in embryonic SC neurons may play a role in the early development of mammalian locomotor networks. SIGNIFICANCE STATEMENT The developing spinal cord (SC) exhibits spontaneous network activity (SNA) involved in the building of nascent locomotor circuits in the embryo. Many studies suggest that SNA depends on the rhythmic release of GABA, yet intracellular recordings of GABAergic neurons have never been performed at the onset of SNA in the SC. We first discovered that embryonic Renshaw cells (V1 R ) are GABAergic at E12.5 and spontaneously active during SNA. We uncover a new role for persistent sodium currents ( I NaP ) in driving plateau potential in V1 R and in SNA patterning in the embryonic SC. Our study thus sheds light on a role for I NaP in the excitability of V1 R and the developing SC., (Copyright © 2018 the authors 0270-6474/18/387667-16$15.00/0.)