The growing aging population of the EU predicts a steady increase in the health and economic burden of mental decline. Hence, the study of the molecular basis of long-term memory formation is a central topic in neuroscience with forseeable social implications. The Erk1/2 MAPK signaling pathway has been strongly implicated in the consolidation of episodic, hippocampus-dependent memories, and it also supports lasting forms of neuroplasticity. However, knowledge on neuronal Erk1/2 signaling is largely limited to mechanisms of activation. If left unchecked, Erk1/2 activation can be detrimental to cognition. It is therefore crucial to understand what intracellular processes rapidly inactivate Erk1/2 following stimulation by synaptic activity, and how they contribute to memory endurance and precision. Furthermore, although Erk1/2 couples to CREB activation, the role of CREB-mediated transcription in memory allocation is poorly defined. It is also not known how the multiple synaptic inputs innervating the hippocampus support memory-associated MAPK signaling. I propose to implement a multidisciplinary approach that will experimentally address these related gaps. We will explore novel forms of Erk1/2 regulation, from the role of tyrosine phosphatases to afferent neural projections and cellular ensembles. To achieve these goals, we will use a combination of transgenic mice, viral vectors for opto- and chemo-genetics, behavioral assays, biochemistry, and confocal imaging. These studies will yield basic insights into molecular mechanisms of memory and hippocampal physiology.