ABSTRACT During development, neural progenitors divide to produce nascent neurons, which migrate and extend axons and dendrites. These neurons form synapses with their neighbors and begin to assemble functional circuits, which mature as synaptic connectivity is refined and additional neurons are integrated into these circuits. Defects in these assembly processes can result in a broad range of problems, including visual processing disorders. Protocadherin-17 (Pcdh17) is a homophilic cell adhesion molecule that is important for collective outgrowth of amygdala axons and to mediate contact-dependent axon growth in vitro, as well as short-term synaptic plasticity. Our preliminary data show circuit-level defects in the optic tectum of the larval zebrafish, with a decrease in the proportion of direction selective neurons and an increase of non-selective neurons. We also provide data showing that neurons of the optic tectum can fasciculate and co-arborize during circuit formation. We hypothesize that loss of Pcdh17 adhesion results in altered patterns of arbor growth and synaptogenesis, which degrades the selectivity of neuronal responses. In this developmental/exploratory R21, we will examine: 1) the developmental trajectory of visual responses in pcdh17 mutants to better define when and how these responses diverge from wild type larva, and 2) the developmental trajectories of axonal and dendritic arbor growth and synaptogenesis in wild type and mutant larvae. These results could reveal a novel cellular mechanism for the assembly of local circuitry and provide insight into how cellular growth processes govern the maturation of neural responses.

NARRATIVE Visual processing disorders are deficits that can affect children's ability to learn, yet the molecular and cellular origins of these developmental disorders is unknown. Protocadherin-17 is part of a family of homophilic cell adhesion molecules, and mutations in human PCDH17 are associated with major mood disorders. We show that pcdh17 mutant zebrafish have defects in visual processing; elucidating the role of pcdh17 in visual system developent could provide insight into visual processing disorders.