Francisco Alvarez (Advisor), Steven Berberich (Committee Chair), Timothy Cope (Committee Member), David Ladle (Committee Member), Robert Putnam (Committee Member)
Doctor of Philosophy (PhD)
The development of locomotion is believed to result from the maturation of the spinal circuits controlling motor output, however little is known about its mechanisms. To shed some light into this process we studied the development of the synaptic connectivity of two spinal inhibitory interneurons. Adult motoneurons are controlled by inhibitory networks that include recurrent and reciprocal inhibition (Pierrot-Deseilligny & Burke, 2005). Each is modulated by different ventral horn spinal interneurons that display synaptic connectivity adapted to their function: Renshaw cells (RCs) mediate recurrent inhibition, receive excitatory inputs from motor axons and inhibit homonymous and synergistic motoneurons; while Ia inhibitory interneurons (IaINs) mediate reciprocal inhibition, receive inputs from Ia proprioceptive afferents and inhibit antagonist motor pools. RCs and IaINs both derive from a homogenous class of embryonic ventral interneurons denominated "V1", leading us to question whether motor axons and Ia afferents target V1 interneurons during early development, followed by postnatal de-selection of specific inputs and generation of cells with typical RC/IaIN connectivity. Using immunohistochemistry, confocal microscopy, 3D neuronal reconstructions and transgenic animal models expressing V1-IN lineage markers, we analyzed synaptic input development on V1-derived RCs and IaINs. We found that motor axons specifically target RCs, are established in early embryo and maintained throughout development. In contrast, Ia afferents contact both IaINs and RCs in late embryo and throughout postnatal development. Ia afferent synapses are de-selected from RCs coinciding with maturation of weight-bearing locomotion. However, Ia afferent inputs on IaINs always occurred at a higher density and were more proximally located than on RCs, suggesting a stronger bias for IaINs. We concluded that there are fundamental differences between IaINs and RCs in their competence for receiving and maintaining motor and Ia afferent inputs. Finally, we investigated the possible role of "transient" Ia afferent inputs on RCs by studying RC connectivity in three genetic animal models that lack Ia afferents, or have weakened/strengthened Ia afferent inputs. We found interactions between Ia afferent strength and motor axon input density on RCs, but not with other excitatory inputs, suggesting that early Ia afferent inputs contribute to shape the organization of motor synapses on RCs.
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