The long-term goal is to elucidate anatomical and molecular mechanisms enabling functional plasticity of representational maps in cerebral cortex. Our current focus is on determining the role of adhesion molecules in establishing the synaptic cortical circuitry upon which topographic maps of the sensory-motor periphery are based. The model system we use is the thalamic projection to rodent somatosensory (barrel) cortex, where two different thalamic inputs (VB and POrn) converge onto layer IV, terminate in mutually exclusive domains, and thereby establish the barrel center/septal organization. We investigate the role of the cadherin family of adhesion proteins in guiding the development and synaptic specificity of these two converging inputs, since cadherins are bona fide adhesion proteins located at the synapse, and have been implicated in synaptic targeting and plasticity. Initial studies showed N-cadherin was present at VB thalamocortical synapses during the period of thalamic axon ingrowth and formation of whisker-related clustering, and suggest that cadherin-8 plays a similar role in establishing the POrn input to septa. We hypothesize that N-cadherin and cadherin-8 provide a dual, adhesive code for specifying these converging inputs. To extend this work, Aim 1 tests functional roles of N-cadherin in establishing the VB thalamocortical projection. Cocultures combined with N-cadherin blocking reagents test roles in axon ingrowth, laminar targeting to layer IV, and synapse formation. In vivo studies test roles in map formation and in modulating neurophysiological properties of thalamocortical synapses.
In Aim 2, we have three sets of studies to test the role of cadherin-8 in development of the POrn thalamic input. First, we will describe the normal development of POrn inputs, since this has never been investigated and will provide a solid foundation for subsequent molecular analyses. Second, we combine immunolocalization methods and direct labeling of POrn thalamic axons and terminals to investigate the relationship between cadherin-8 localization and development of the thalamic input and of barrel center/septal architecture. These studies will provide an essential anatomical framework for investigating functional roles of cadherin-8, which is the experimental focus of the third set of studies. Here, we use cocultures and cadherin-8 blocking reagents to begin investigating functional roles of cadherin-8 in development of the POrn input. Taken together, our studies will provide three significant advances: first, new details of the mechanisms by which cadherins orchestrate the development of highly organized cortical synaptic circuits in a mammalian model of cortical map formation; second, new, normative details about how the thalamic whisker maps develop, which will provide fundamental information on a model system which is an archetype for cortical development and plasticity; third, results will lay the groundwork for advancing our understanding of the role of cadherins in axon growth and synaptic remodeling which may underlie long-term cortical map plasticity during learning or resulting from injury.
