The long term goals of this study are to characterize the cellular interactions that are necessary to form functional synapses between neurons. Although the questions asked are basic, they have important medical ramifications, since defects in cellular interactions during growth and synapse formation would create a highly disordered nervous system. If these cellular interactions were understood, it would pro- vide a rational basis from which to design therapeutic interventions. The approach is to characterize the cellular properties of neurons developing in vitro, since this allows for a high degree of experimental control and manipulation that is not possible in the developing brain. In the experiments described here, cellular interactions will be examined in two different neural systems. Sympathetic preganglionic neurons (SPN) project from the spinal cord to sympathetic ganglion neurons, and play a crucial role in the neural control of autonomic functions, such as heart rate and blood pressure. The neurons of the cerebellum have a major role in motor control, and damage to the cerebellum has been implicated in many neurological problems, both non- hereditary and hereditary. These studies are thus of direct relevance to understanding disorders of the developing nervous system. In the current grant period there are three major goals. Goal 1- The growth cones of SPN react differently to contact with three types of cells they are likely to encounter during their growth to the periphery. In these experiments the hypothesis that different growth cone behaviors are mediated by different second messenger systems will be tested. The possibility that changes in intracellular free calcium concentration mediate one or more of the specific behaviors exhibited by SPN growth cones will be given special attention. Goal 2- Following the initial contact of an SPN with a sympathetic ganglion neuron there is a delay of many hours before the onset of synaptic function. In these experiments the hypothesis that the formation of one synapse by an SPN enhances the ability of that neuron to make additional synapses will be tested. Goal 3- In these experiments the hypothesis that glutamatergic neurons regulate the expression of specific subtypes of glutamate receptors will be tested. This hypothesis was suggested by studies conducted on SPN, but cannot be easily tested on these neurons. Instead, cultures of cerebellar neurons with and without brain stem afferents will be used.
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