Molecular labels that instruct specific synapse formation

One of the major questions within the field of Molecular Neuroscience is how different neurons are able to locate and form synapses specifically with their appropriate targets so that functional neural circuits are generated. Two quite different mechanis ms appear to be involved. One is an activity-dependent mechanism in which ongoing patterns of activity drive some synapses more than others. In general, pre- and postsynaptic neurons that are co-active tend to form synapses with each other, and the most a ctive synapses tend to be stabilized, whereas the least active tend to be eliminated. This activity-dependent mechanism underlies for example the formation of sensory projections during development, as well as their ongoing modification throughout life. The other mechanism involves specific cell-cell recognition, which must be mediated by molecular addresses on the pre- and postsynaptic neurons. We have studied synapse formation in the vestibulo-ocular reflex pathway, and have for the first time managed to make a dynamic characterization of the functional development of an entire polysynaptic reflex circuit in any species. We have moreover been able to assess the effects of endogenous activity and manipulations of activity (spontaneous synchronous activ ity and chronic blockade of NMDA receptors). Our results demonstrate that the synaptic connections of the VOR circuit are established correctly from the outset despite patterns of activity that are known to dramatically disrupt specificity in sensory proj ections. Thus, we have obtained strong support for the idea that connections in this and other reflex motor circuits are specified not by activity but by molecular addresses. The goal of this project is to use molecular biological techniques such as micro arrays, subtraction hybridization and real-time PCR to identify the molecular addresses involved, and then use high-resolution immunohistochemistry to map the localization of these molecules during synaptogenesis.