The rules governing synaptic metaplasticity (the plasticity of plasticity) are of special importance in the developing nervous system, where experience has an important role in the patterning of neural responses and the influence of prior synaptic activity on future synaptic change can have profound consequences. We have developed and employed a fosGFP transgenic mouse to identify the locus of experience-dependent change in somatosensory neocortex. In control animals, NMDAR-dependent LTP can be generated at layer 4-2/3 synapses in vitro, and normal experience results in the progressive strengthening of these synapses over the second and third postnatal week. Whisker stimulation enhances synaptic strength and leads to a transformation in the molecular mechanisms that underlie plasticity, from NMDAR-dependent to mGluR-dependent potentiation. This proposal seeks to identify how cumulative, experience-dependent plasticity is initiated and maintained by the activation by specific subtypes of glutamate receptors, using both in vivo and in vitro analysis. PUBLIC HEALTH RELEVANCE: Learning frequently takes place over repeated stimulus presentations and is cumulative over time, especially in the neocortex. The cellular and molecular basis for this type of cumulative synaptic change requires identification and analysis of the specific synapses that are undergoing continuous modifications. Using a fosGFP transgenic mice to locate the precise area of the neocortex where plasticity is occurring, we can identify the synaptic substrates of experience-dependent plasticity and determine the molecular mechanisms that are invoked during this form of learning. We have found that the direction of NMDAR-dependent plasticity is reversed after the onset of experience-dependent plasticity in sensory neocortex, and that subsequent synaptic strengthening requires activation of mGluRs. The molecular mechanisms by which experience alters the function and localization of glutamate receptor subtypes is of essential interest to studies of learning and memory.