Saturday, April 27, 2024
4/27/2024
Electrical synaptic transmission via gap junctions (GJs) is an important mode of neuronal communication in the CNS. An elegant example is the retina in which each of the five main neuronal types is electrically coupled via GJs. The broad distribution, diverse connexin subunit structure, and regulation of retinal GJs suggest a diversity of functional roles in visual processing; elucidating these roles forms the long-term goal of our experimental program. Here we propose to study the GJs in the inner mouse retina, which subserve a rich and complex variety of electrical circuits. The first aim of this proposal is to determine the role of cell-to-cell vs. neuron ensemble interactions in creating the robust, correlated activity displayed by retinal ganglion cells (RGCs). Correlated RGC activity is believed to have a number of functions, including enhancement of signal saliency and encoding of specific information about visual stimuli such as intensity, size, and motion. While it is now clear that GJs are critical to the creation of the robust concerted activity between RGC neighbors, the exact mechanism remains unclear. While it has been posited that reciprocal drive between coupled RGC neighbors can produce concerted firing, our preliminary data suggest that this does not occur. Rather, it appears that coherent activity within neuronal ensembles is necessary to recruit additional RGCs and produce their coherent activity. We propose a multidisciplinary approach combining electrophysiological, pharmacological, and optogenetic techniques applied to transgenic and knockout mouse lines to differentiate the circuits responsible for correlated RGC activity. The second aim will focus on the coupling between RGCs and amacrine cells (ACs). This type of electrical coupling occurs extensively across the retina, but how this affects neuronal activity has not been studied comprehensively due to a lack of an experimental platform to visualize and target coupled RGC-AC pairs for recording. We will target coupled RGC-AC pairs using two techniques: (1) labeling cells with the GJ-permenat dye Po-Pro-1; and (2) using the transgenic Grik4 mouse line in which ON a-RGCs and coupled ACs express fluorescent markers. For both, we will record from coupled pairs of RGCs and ACs to determine the role that this electrical interaction has on the response activity of inner retinal neurons. In the third aim we will study the novel idea that RGCs can alter intraretinal activity by signaling back to AC through interconnecting GJs. We posit that RGCs can alter the activity of coupled ACs, which, in turn, inhibit other ganglion cells via conventional chemical synapses. This form of intraretinal signaling thereby creates a circuit providing a novel form of lateral inhibition. Deficits in GJ communication have been implicated in a number of brain neuropathies, including visual impairments associated with retinitis pigmentosa, glaucoma and ischemic retinopathy. The experimental program proposed here will extend our understanding of the distribution and physiological roles of GJs, which forms an important prerequisite for determining how GJ dysfunction affects neural function so as to indicate novel targets for the treatment of human diseases.
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