THE EMBRYONIC NEURAL CIRCUIT: MECHANISM AND INFLUENCE OF SPONTANEOUS RHYTHMIC ACTIVITY IN EARLY SPINAL CORD DEVELOPMENT

Over the last several decades, a general consensus has emerged that molecular mechanisms are required for proper axon pathfinding and initial circuit formation while activity dependent mechanisms primarily regulate the synaptic refinement important for proper connectivity of the circuit. Shortly after motoneurons are born, they begin to extend axons into the periphery and make early pathfinding decisions. Experiments described within this thesis demonstrate that spontaneous rhythmic bursting episodes of electrical activity as well as spontaneous unit activity could be recorded from these extending axons. Therefore, this spontaneous rhythmic activity during initial outgrowth might play an important role in early axonal decisions. In order to test this hypothesis, it was first essential to characterize the cellular mechanisms required for the initiation and propagation of these episodes. Experiments further demonstrated that the motoneurons, via cholinergic transmission, are essential for the production of this early spontaneous activity but that GABA and glycine acting in an excitatory manner also contribute. With this detailed characterization of the circuit that generates this activity, it was possible to pharmacologically alter the frequency of the spontaneous rhythmic episodes in ovo during precise stages of development while maintaining spontaneous unit activity. Altering the frequency of rhythmic bursting activity during early pathfinding at the nerve plexus not only induced motor axon pathfinding errors, but also altered the expression of EphA4 and polysialic acid on NCAM (PSA), molecules known to be required for early pathfinding. Thus, this work illustrates that both early motor axon pathfinding and the expression of specific guidance molecules is dependent on spontaneous rhythmic episodes of activity from the spinal cord.