AMPA-type glutamate receptors (AMPARs) are ligand-gated sodium channels. Through their ability to mediate the majority of rapid excitatory transmission in the CNS, these neurotransmitter receptors have been shown to influence synaptic plasticity. Some of these receptors are also calcium permeable (CP), and they also have been implicated in regulating synaptic plasticity, particularly in interneurons where their concentration is highest. However, the biochemical pathways emanating from CP-AMPARs that mediate these effects are not well characterized. In this paper, we show that CP-AMPARs are the predominant AMPAR class responsible for activating the Ras/Erk kinase signaling cascade and the CREB transcription factor in the cortex of mature mice. Activation of Ras and Erk, but not CREB, occurs through the calcium/calmodulin regulated Ras-GRF1 and Ras-GRF2 exchange factors, which form AMPA-induced complexes with CP-AMPARs but not calcium impermeable (CI)-AMPA receptors in vivo. Furthermore, we show that CP-AMPARs are also the major AMPAR type to activate Ras/Erk signaling in pubescent mice, however at this developmental stage Ras-GRF proteins are not involved. Finally, in neonatal animals CI-AMPARs, not CP-AMPARs, are the predominant AMPAR type that activates Ras-Erk signaling and CREB in cortical neurons. This occurs indirectly through activation of L-type voltage-dependent calcium channels, an event that is also Ras-GRF independent. Thus, Ras/Erk signaling and CREB activity induced by AMPARs occur through age-dependent mechanisms that likely make unique developmentally-dependent contributions to synaptic function.