Characterization of the Circuits That Generate Spontaneous Episodes of Activity in the Early Embryonic Mouse Spinal Cord

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Abstract
In the developing nervous system, patterned spontaneous activity affects a variety of developmental processes. Thus, it is important to identify the earliest time that such activity occurs and to characterize the underlying circuitry. In isolated mouse spinal cord–limb preparations, highly rhythmic spontaneous activity occurred as early as embryonic day 11 (E11)–E12, when many lumbosacral motoneurons were still migrating and extending their peripheral projections. This activity required both electrical and chemical transmission, and acetylcholine, rather than glutamate, provided the main excitatory drive. Our data are consistent with motoneurons themselves playing a critical role in generating such activity by making excitatory connections on each other and on GABAergic interneurons via dihydro-β-erythroidine hydrobromide (DHβE)-insensitive nicotinic receptors. This resulted in the generation of local bursts. Consistent with these observations, E12–E12.5 mouse motoneurons retrogradely labeled by HRP were observed to have extensive axon collaterals that projected locally within the lateral motor column and to interneuron-containing regions dorsal and medial of the lateral motor column. Cholinergic axons, presumably from motoneurons, were also observed in the ventral and lateral funiculi. However, for local bursts to propagate throughout the cord, a second DHβE-sensitive cholinergic pathway that also involved glycinergic interneurons was required. This circuit characterization should facilitate the use of genetic mutations that alter specific subpopulations of interneurons or cholinergic transmission to determine how modifying different aspects of this early activity affects subsequent development of the spinal motor circuit.