Age-dependent participation of Ras-GRF proteins in coupling calcium-permeable AMPA glutamate receptors to Ras/Erk signaling in cortical neurons.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors (AMPARs) are ligand-gated sodium channels. Through their ability to mediate the majority of rapid excitatory transmission in the central nervous system, 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 have not been 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 cAMP-response element-binding protein (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) AMPARs 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 (guanine nucleotide-releasing factor) proteins are not involved. Finally, in neonatal animals CI-AMPARs, but 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.