Brain function, from sensory perception to behavior, is derived from the pattern and properties of the synaptic connections among hundreds (in C. elegans), hundreds of thousands (in Drosophila), or even billions (in humans) of individual neurons. I am interested in three broad but related questions: by what cellular and molecular mechanisms do neurons form synapses only with the correct neuronal partners, how are the specialized pre- and post-synaptic structures assembled into functional connections, and how are these connections organized to form functional neural circuits?
I propose to address these questions using the Drosophila visual system. Fly photoreceptor neurons (R cells) face tasks of target selection and synapse formation similar to those faced by vertebrate neurons: each class of R cell makes synapses that are restricted to a different layer of the underlying optic ganglia; the topographical arrangement of the R cell synapses within each layer recapitulates the arrangement of their cell bodies in the retina; and this final retinotopic pattern of synapses is achieved by interactions among neighboring R cells.
I have begun the identification and analysis of genes required for synaptic target selection by a subset of R neurons, the R7s, taking advantage of a unique combination of powerful tools: the ability to create homozygous mutant R7s in an otherwise wild-type animal; to select mosaic animals with non-functional R7s (the primary sensors of UV light) by means of a robust behavioral assay (a failure to phototax toward UV in preference to green light); and to analyze histologically the synaptic connections of mutant R7s in an otherwise wild-type animal. This novel screen has successfully identified genes required for formation of R7 synapses in the correct target layer and genes required for restriction of R7 synapses to discrete, retinotopically correct targets within that layer. I propose to continue to use these methods to complete a molecular understanding of R7 target selection and synaptogenesis.
Synapse formation involves bidirectional signaling between axon and target to coordinate the assembly of pre- and post-synaptic specializations. The identities of the cells that cue R7s to terminate in the correct layer are unknown, as are the identities of the cells upon which R7s synapse in the adult (it is unclear at this point whether these two categories of cells will be the same). I propose to develop the tools to identify and genetically manipulate the R7 targets as easily as it is now possible to manipulate R7. Such tools will allow the identification of genes required post-synaptically for R7 target selection and synaptogenesis and may allow us ultimately to dissect the neural circuit for the discrimination of UV from other colors of light.
(pulled from pubmed)