Early postnatal development of reciprocal Ia inhibition in the murine spinal cord. J Neurophysiol 100: 185-196, 2008. First published May 7, 2008 doi:10.1152/jn.90354.2008. The pathway mediating reciprocal inhibition from muscle spindle afferents (Ia axons) to motoneurons (MNs) supplying antagonist muscles has been well studied in adult cats, but little is known about how this disynaptic pathway develops. As a basis for studying its development, we characterized this pathway in mice during the first postnatal week, focusing on the projection of quadriceps (Q) Ia axons to posterior biceps-semitendinosis (PBSt) MNs via Ia inhibitory interneurons. Synaptic potentials in PBSt MNs evoked by Q nerve stimulation are mediated disynaptically and are blocked by strychnine, implying that glycine is the major inhibitory transmitter as in adult cats. The specificity of neuronal connections in this reflex pathway is already high at birth; Q afferents evoke inhibitory synaptic potentials in PBSt MNs, but afferents supplying the adductor muscle do not. Similar to this disynaptic pathway in cats, Renshaw cells inhibit the interposed Ia interneurons, as they reduce the disynaptic input from Q axons but do not inhibit PBSt MNs directly. Reciprocal inhibition functionally inhibits the monosynaptic excitatory reflex in PBSt MNs by P3, but this functional inhibition is weak at P1. Finally, deletion of the transcription factor Pax6, which is required for the development of V1-derived Renshaw cells, does not block development of this pathway. This suggests either that Pax6 is not required for the phenotypic development of all V1-derived spinal interneurons or that these inhibitory interneurons are not derived from V1 precursors.

Muscle sensory axons induce the development of specialized intrafusal muscle fibers in muscle spindles during development, but the role that the intrafusal fibers may play in the development of the central projections of these Ia sensory axons is unclear. In the present study, we assessed the influence of intrafusal fibers in muscle spindles on the formation of monosynaptic connections between Ia (muscle spindle) sensory axons and motoneurons (MNs) using two transgenic strains of mice. Deletion of the ErbB2 receptor from developing myotubes disrupts the formation of intrafusal muscle fibers and causes a nearly complete absence of functional synaptic connections between Ia axons and MNs. Monosynaptic connectivity can be fully restored by postnatal administration of neurotrophin-3 (NT-3), and the synaptic connections in NT-3-treated mice are as specific as in wild-type mice. Deletion of the Egr3 transcription factor also impairs the development of intrafusal muscle fibers and disrupts synaptic connectivity between Ia axons and MNs. Postnatal injections of NT-3 restore the normal strengths and specificity of Ia-motoneuronal connections in these mice as well. Severe deficits in intrafusal fiber development, therefore, do not disrupt the establishment of normal, selective patterns of connections between Ia axons and MNs, although these connections require the presence of NT-3, normally supplied by intrafusal fibers, to be functional.