The long term goal of this project is to define the glutamate receptor subtypes associated with synapses in the cerebellar cortex and to elucidate the role of these receptor subtypes in nitric oxide production. Although it is known that multiple glutamate receptor subtypes exist in the cerebellar cortex, the specific subtypes associated with different parallel fiber versus climbing fiber synapses remains to be defined. There is currently no information available as to whether the number or subtypes of glutamate receptors differ between synapses located in zebrin positive parasagittal binds versus zebrin negative bands. The proposed studies will test the hypothesis that: 1) Glutamate receptor subtypes differ between the parallel fiber/Purkinje cell synapse and the parallel fiber/stellate cell synapse and between the parallel fiber/Purkinje cell and climbing fiber/Purkinje cell synapses; and 2) Climbing fiber activation causes nitric oxide (NO) production in the cerebellar cortex via activation of glutamate receptors on stellate cells, while parallel fiber activation produces NO directly.
In Specific Aim 1 the first hypothesis will be tested by using immunocytochemistry and electron microscopy to determine the molecular subtypes of glutamate receptors associated with climbing fiber and parallel fiber synapses.
In Specific Aim 2 the second hypothesis will be tested by using electrical or chemical stimulation of climbing and parallel fibers in combination with in vivo microdialysis and administration of glutamate receptor antagonists. These studies will provide new data on the synaptic distribution of glutamate receptors in the mouse and rat cerebellar cortex and will determine if differences in receptor subtypes exist between zebrin positive and zebrin negative parasagittal bands. In addition these studies will elucidate the glutamate receptor subtypes involved in cerebellar NO production in vivo. This neurochemical information is important for understanding the basic mechanisms that underlie parallel and climbing fiber neurotransmission and those involved in cerebellar NO release.
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