This proposal seeks to understand the network and cellular basis of serotonin's action in the mammalian retina. Serotonin-containing neurons or serotonin-accumulating neurons are found in most retina, including human. In mammals, they are reciprocally connected to the rod bipolar cell; it has been suggested that they gate the output of the rod bipolar cell. This application seeks to critically examine several aspects of this hypothesis. Two preparations of the retina will be used: an eyecup preparation and dissociated retinal neurons. The role of serotonin in both light- and dark-adapted retinae will be examined with extracellular recording techniques from ganglion cells in the intact rabbit retina. The effects of selective antagonists and agonists on the ON and OFF responses will be observed. In addition to testing changes in the magnitude of ganglion cell responses, changes in responsitivity and sensitivity will be studied using response-intensity data and incremental threshold. The site of action of serotoninergic drugs will be confirmed with drugs whose sites of action in the rod pathway have been proven. To study the cellular basis of serotonin action on retinal neurons, a dissociated cell culture preparation will be used. In these experiments, whole-cell recordings will be used to define the currents associated with serotonin receptor activation. Specific serotoninergic agonists will be used to identify the subtypes of receptors involved. The mechanisms of coupling receptors to ion channels will be explored. Finally, the cellular localization of the neuronal high-affinity serotonin transporter will be identified by immunohistochemical and pharmacological techniques in the rabbit retina. This work has direct significance to rod information processing and thus may be relevant to clinical conditions affecting night vision. Serotonin is a widely distributed CNS neurotransmitter; it is implicated in a variety of disease states including sleeping disorders, chronic anxiety and depression. Pharmacological manipulations of the retina have been proven to be of general significance to the mechanism of neurotransmitter function in the CNS. This proposal seeks to couple a cellular understanding of transmitter action with its network role.
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