Amacrine Cell Function in the Retina

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DESCRIPTION (provided by applicant): Like other CNS loci, the major mode of cellular communication in the mammalian retina is via chemically-mediated synaptic transmission. However, work over the last decade indicates that electrical synaptic transmission, via gap junctions, forms a second significant mode of neuronal interaction in the retina. It is now clear that gap junctions are ubiquitous throughout the retina, occurring between cells within each of the five major cell classes. In addition, retinal gap junctions have been shown to be dynamically regulated by changes in ambient illumination and circadian rhythms acting through light-activated neuromodulators such as dopamine and nitric oxide. These data suggest that gap junctions play a key role in light adaptation. The networks formed by electrically coupled retinal neurons thus provide plastic, reconfigurable circuits for the flow of visual signals. Overall, direct intercellular communication via electrical coupling is positioned to play key and diverse roles in the transmission and integration of visual information at every retinal level. The long-term goal of this research is to define the distribution, function and regulation of the gap junctions in the mammalian retina so as to understand their roles in the transmission of visual information. Accordingly, the specific aims of this proposal include: (1) to determine the roles of the different gap junctions that form crucial elements in the different rod pathways; (2) to determine the roles of ganglion-to-ganglion cell and ganglion-to-amacrine cell electrical coupling in the synchronization of the spike activity of neighboring alpha ganglion cells and whether this is regulated by light; and (3) to elucidate the different subtypes of amacrine and ganglion cells that form distinct and stereotypic coupled networks in the proximal mammalian retina. A final aim is to define the structure and function of amacrine cell types, long a focus of the work in our lab, to provide a framework to understand the role of their electrical junctions. The functions of gap junctions will be assayed electrophysiologically by recording from retinal neurons under conditions in which gap junctions are disrupted either pharamcologically or in a connexin36 knockout mouse model. In addition, the biotinylated tracer Neurobiotin, which can pass through gap junctions, will be used to morphologically assay changes in the extent of coupling so as to determine how it is regulated by light or disrupted in the experimental models. Gap junctions have been implicated in a number of neurological diseases including X-linked Charcot-Marie-Tooth disease, nonsyndromic autosomal deafness as well as having a role in neuroprotection and cell loss following stroke or trauma. Although focused on the function and regulation of gap junctions in the mammalian retina, the proposed work should nevertheless provide important insights into the roles and plasticity of gap junctions throughout the brain.