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 great importance for neural circuit formation, function and dysfunction. Adult interneurons are characterized by specific synaptic inputs and outputs and a major unresolved question is the interrelationship between genetic factors and activity dependent mechanisms 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 development 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"""""""" interneurons generated in embryo. Our long-term objective is to understand how synaptic inputs are differentially selected and mature on the large diversity of spinal interneurons that form the spinal cord motor synaptic circuits. Dysfunction of this synaptic network, including errors in its development, leads to motor abnormalities in adults and newborns. The etiologies of many of these syndromes are currently unknown. We propose to investigate the emergence of adult synaptic organization on interneurons derived from one subclass of embryonic interneurons, the V1 group. Using transgenic mice that express either lacZ or GAP43-EGFP in the soma or axons of Vl-derived interneurons we will be able to follow their location, structure and development from birth to adulthood. Our preliminary data suggests that Vl-derived interneurons give rise to several adult spinal cord lastorder inhibitory interneurons and, 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 structure is stabilized and matured postnatally over the V1 genetic background through activity-dependent mechanisms, and as a consequence V1- interneurons diversify into several adult subtypes. To test the hypothesis we propose to 1) identify the characteristics of adult Vl-derived neurons, 2) study the normal development of each synaptic input onto Vl-neuron subgroups giving rise to Renshaw cells and lalNs, 3) study the ultrastructural and molecular maturation of both inputs, and 4) test the effect of experimentally biasing either glutamatergic transmission or cholinergic motor axon activity during postnatal development on Vl-interneuron synaptic organization. We will also examine temporal patterns of expression of neurotrophins and trk receptors in V1- interneurons that could contribute to these processes. ? ?
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