Elucidating synaptic motifs in the visual thalamus

PROJECT SUMMARY The sensory thalamus serves as a hub for incoming information encoding different features of the outside world. This information is parsed and modified as it is transmitted to the cortex. In the visual thalamus (the dorsal lateral geniculate nucleus), retinal ganglion cell axons converge onto proximal dendrites of thalamocortical neurons, forming clusters of boutons that stud the dendrites. Many of these bouton clusters are ensheathed by astrocytes along with synaptic terminals from neuromodulatory projections and inhibitory dendrodendritic presynaptic terminals. Collectively, this synaptic motif is called the glomerulus, described beautifully by electron microscopy in many thalamic nuclei and across many species. While the glomerulus is quite striking, the functional relevance of this structural motif is still debated. To address this critical question, here, we propose to establish and characterize mice in which the glomerular astrocytic sheath is disrupted by genetic deletion of a member of the family of fibroblast growth factor receptors. Our preliminary data shows that deletion of this receptor from astrocytes results in reduced astrocytic sheaths around clusters of retinal ganglion cell boutons and aberrant retinogeniculate functional refinement. We will extend these findings to elucidate the role of this receptor in the development of astrocytic morphology, glomerular structure and the elimination and strengthening of retinogeniculate synapses in the visual thalamus. We will also examine whether and how defects in astrocytic ensheathment of the glomerulus may contribute to aberrant retinogeniculate synapse refinement. Finally, we will take advantage of the disrupted glomerular ensheathment in mutant mice to test the hypothesis that the glomerular structure enhances crosstalk between synapses within the astrocytic sheath that is mediated by glutamate and GABA spillover. If these proposed experiments are successful, results from these studies will advance our understanding of how information is organized in the thalamus and the functional sequela of disruption of this organization.