The role of classic cadherins in the development of hippocampal circuitry

Development of precise neuronal connections is crucial for proper brain functioning. To achieve this stereotyped connectivity involves many different processes: neurogenesis, neuronal migration, neuronal differentiation, axonal guidance, target specificity and formation of synaptic contacts. This dissertation focuses on the last steps of connectivity: process outgrowth, target and synaptic specificity. Current theory suggests that synapse formation and specificity is generated by a multi-step, hierarchical process involving several different major families of proteins.; Cadherins are excellent candidates in mediating both target and synaptic specificity. The diversity and specificity of cadherin structure and function, their localization at the synapse and their spatiotemporally restricted patterns of expression in multiple brain regions and functional systems brings forth the hypothesis that cadherins account for the connectivity between neurons in the brain.; This hypothesis was tested by looking at the role of classic cadherins in the development of hippocampal circuitry. We identified nine different classic cadherins which are expressed in the hippocampus during the principal period of synaptogenesis. Analysis of the spatiotemporal distribution patterns of N-cadherin, cadherin-6, cadherin-8, cadherin-9 and cadherin-10 in limbic system areas showed that each cadherin is differentially distributed in distinct, but highly overlapping fields that correspond to known anatomical boundaries and are often coordinately expressed in interconnected regions. These studies suggest that more than one classic cadherin may be important in providing specificity of developing connections.; To further investigate how cadherins play a role in developing specific connections, we focused on hippocampal mossy fiber development, since this circuit develops in a highly stereotyped manner restricted by laminar, regional and subcellular boundaries. We show that both N-cadherin and cadherin-8 are expressed in dentate granule cells and CA3 pyramidal neurons. Using function blocking reagents, we show that N-cadherin promotes mossy fiber outgrowth, while cadherin-8 inhibits it. We also show that both cadherins are required for mossy fiber laminar and regional specificity. Finally, we show that both cadherins are important for synapse formation in all lamina in the CA3 region. In conclusion, our data suggests that at least N-cadherin and cadherin-8 can mediate mossy fiber laminar, regional and subcellular specificity.