Retinal inputs signal through astrocytes to recruit interneurons into visual thalamus

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Currently there are no effective treatments for patients with deficits in subcortical visual circuits. In response to this unmet need, NEI has issued an Audacious Goals Initiative with the goal of gaining new knowledge that will contribute to the development of regenerative therapies aimed at restoring subcortical visual circuits. To accomplish this goal, we need a better understanding of the cell and molecular mechanisms that drive the formation of these circuits during development. Although we have made progress in our understanding of how retinal axons target and innervate subcortical brain regions (such as the dorsal and ventral lateral geniculate nuclei [dLGN and vLGN, respectively]), we lack critical knowledge about how other inputs and cells target these regions. Inputs from the cortex, thalamic nuclei, brainstem nuclei and local interneurons act as modulatory or inhibitory inputs in visual thalamus and play essential roles in the processing of visual information. These inputs far outnumber retinal inputs in visual thalamus. Interestingly, the recruitment and incorporation of these non-retinal inputs (and cells) into thalamic circuits are regulated by retinal inputs. For example, retinal inputs are necessary for the recruitment of GABAergic interneurons into visual thalamus and the incorporation of their inputs into visual circuits. This is critical since these inhibitory synapses enhance spatial and temporal selectivity of visual information as it is transmitted through the thalamus. At present we lack a clear understanding of the mechanisms through which retinal inputs influence GABAergic neuron recruitment and incorporation into visual thalamus. This proposal specifically addresses this question by testing whether a novel axo-glial-neuron signaling pathway exists in visual thalamus. Specifically, we will test whether retinal axons release SHH to induce astrocyte expression of FGF15, and whether astrocyte-derived FGF15 is necessary for interneuron recruitment into visual thalamus. Identifying the novel axon-glia-neuron signaling pathway proposed here will be a significant step forward in our understanding of the role of glia in thalamic development and in the mechanisms underlying subcortical visual circuit assembly.