A fundamental problem in neurobiology is how mature synaptic circuits emerge postnatally from a complex array of undifferentiated synapses and embryonic neurons. In particular, little is known about the maturation of interneurons, despite their importance for neural circuit formation, function and dysfunction. Our focus in on the development of spinal cord motor circuits. Newborns display immature spinal motor circuits manifest in abnormal reflexes, limited capacity to make effective postural adjustments and higher than normal co-contraction of agonists and antagonists. Little is known about how the spinal interneuronal circuits responsible for the maturation of normal locomotor activity develop. Adult interneurons are characterized by specific synaptic inputs and outputs and a major unresolved question is the interrelationship between genetic factors and environmental influences in the development of these different synaptic architectures. The recent characterization of a few cardinal embryonic interneuron subtypes in the spinal cord, defined by different genetic backgrounds and the generation of transgenic mice expressing lineage markers for these populations, opens the possibility of investigating the development of adult-type interneurons and their synaptic inputs, from a few groups of genetically determined """"""""predecessor"""""""" embryonic interneurons. Our long-term objective is to understand how synaptic inputs are differentially selected and mature on the large diversity of spinal interneurons. We propose to investigate the emergence of adult synaptic organization on interneurons derived from the V1 group of embryonic interneurons. Using transgenic mice that express either lacZ or GAP43-EGFP in the soma or axons of V1- derived interneurons we will be able to follow their location, structure and development from birth to adulthood. Our preliminary data suggests that V1-derived interneurons give rise to several spinal cord last-order inhibitory interneurons, among others, Renshaw cells and la Inhibitory Interneurons (laIN). Interestingly each cell type is characterized by different excitatory synaptic inputs: glutamatergic/muscle afferents preferentially target lalNs while cholinergic/motor axons synapse on Renshaw cells. We hypothesize that this distinctive synaptic organization is stabilized and matured postnatally and as a consequence V1- interneurons diversify into several adult subtypes. We propose the following specific aims 1) identify the characteristics of adult V1-derived neurons, 2) study the normal development of each synaptic input onto V1-neuron subgroups giving rise to Renshaw cells and lalNs, 3) study the ultrastructural and molecular maturation of these inputs, and 4) test the influence of muscle afferent central arborizations in the specification of different interneuronal phenotypes.
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