DESCRIPTION (provided by applicant): The brains of all animals are composed out of individual neurons with cell type specific morphologies. The remarkably diverse dendritic architecture of neurons determines two fundamental aspects of neural circuitry: First, it dictates which presynaptic neurons can contact the postsynaptic dendritic arbor. Second, it affects the summation and computation of synaptic input in the postsynaptic dendritic arbor. Consequently, healthy brain function relies on the correct development of dendritic structure, and dendritic architecture defects have been associated with a number of neurodegenerative diseases, such as Rett- and Fragile-X Syndrome. Identifying the molecular mechanisms that regulate dendritic architecture development and synapse placement on dendritic arbors is imperative to understanding neural circuit development in the healthy and in the diseased brain. Despite recent success in identifying key molecular mechanisms regulating dendritic arbor development, our knowledge on the functional consequences of dendritic architecture mis-regulation for synaptic partner matching and for synaptic input processing in the postsynaptic neuron remains fragmentary. This study aims to unravel molecular mechanisms underlying specific aspects of dendritic architecture development as well as the functional consequences of false regulation. During development dendritic structure is regulated by innate genetic factors, guidance cues, humoral cues, and by neuronal activity. Although some of these signals may be integrated by similar intracellular signaling pathways, different signals can independently affect various dendritic features in the same neuron, such as dendritic branch lengths and numbers, dendritic territory borders, and the correct spacing of dendritic arbors within their territories. During recent years, fundamental new insights into the molecular mechanisms that control dendritic self-avoidance and tiling, and thereby correct dendritic arbor spacing, have come from the Drosophila genetic model system. However, it remains largely unclear how these mechanisms interact with synaptic partner matching during circuit assembly in the central nervous system. Therefore, the proposed experiments will test how dendritic self-avoidance mechanisms interact with central synapse formation during dendritic arbor development of Drosophila motoneurons. A quantitative database on control motoneuron dendritic architecture features will serve as bedrock for testing the roles of key molecules mediating dendritic repulsion by targeted genetic manipulation. In addition, we have identified sensory neurons that synapse onto these motoneurons, allowing one to test for functional interactions between dendritic repulsion and synaptic partner matching during dendritic arbor growth. Furthermore, correct and false dendritic architecture regulation will be related to neuronal function by computational approaches and electrophysiological recordings in control and genetically manipulated animals. We expect to gain novel insight into the regulation of dendritic arbor architecture during development as well as into the functional consequences of dendritic arbor defects in mature neurons.

The correct connectivity of neurons and the computation of synaptic input information within the healthy brain rely crucially on the precise regulation of the morphology of neuronal dendrites during development, and consequently, dendritic architecture defects have been associated with a number of neurodegenerative diseases, such as Rett- and Fragile-X Syndrome. The proposed studies will utilize the genetic tools available in Drosophila to unravel molecular mechanisms that have been conserved from flies to humans to regulate the correct morphological development of neuronal dendrites, as well as the functional consequences of false dendritic architecture development for proper information processing within neurons.