Brief theta-burst stimulation induces a transcription-dependent late phase of LTP requiring cAMP in area CA1 of the mouse hippocampus

Abstract

Memory storage in the mammalian brain can be divided into a short-term phase that is independent of new protein synthesis and a long-term phase that requires synthesis of new RNA and proteins. A cellular model for these two phases has emerged from studies of long-term potentiation (LTP) in the three major excitatory synaptic pathways in the hippocampus. One especially effective protocol for inducing robust and persistent LTP is "theta-burst" stimulation, which is designed to mimic the firing patterns of hippocampal neurons recorded during exploratory behavior in intact awake animals. Unlike LTP induced by non-theta tetanization regimens, little is known about the biochemical mechanisms underlying theta-burst LTP in the hippocampus. In the present study, we examined theta-burst LTP in the Schaffer collateral pathway. We found that 3 sec of theta-burst stimulation induced a robust and persistent potentiation (theta L-LTP) in mouse hippocampal slices. This theta L-LTP was dependent on NMDA receptor activation. The initial or early phase of theta-LTP did not require either protein or RNA synthesis and was independent of cAMP-dependent protein kinase (PKA) activation. In contrast, the late phase of theta-LTP required synthesis of proteins and RNA and was blocked by inhibitors of PKA. Prior induction of theta-LTP also occluded the potentiation elicited by chemical activation of PKA. Our results show that, like non-theta LTP, theta-induced LTP in area CA1 of the mouse hippocampus also involves transcription, translation, and PKA and suggest that cAMP-mediated gene transcription may be a common mechanism responsible for the late phases of LTP induced by both theta and non-theta patterns of stimulation.