Activity-Regulated Gene Expression in the Brain

Neural activity is an essential stimulus for induction of plasticity and normal development of the CNS. Several lines of evidence indicate a role for rapid synthesis of mRNA and protein in long-term neural plasticity. For example, classical studies on learning and memory demonstrate a requirement for protein synthesis in long-term memory. Furthermore, Kandel et al. showed that long-term potentiation (LTP) in the hippocampus is blocked by inhibitors of either RNA or protein synthesis. Immediate early genes (IEGs) are rapidly induced in neurons by synaptic activity and consist of the macromolecular response required for longterm plasticity. We have used differential cloning techniques to identify genes that are rapidly induced by depolarizing stimuli . In contrast to the earlier interest in transcription factors, we have focused on “effector” IEG proteins that directly modify the function of neurons. So far, we analyzed growth factors, enzymes involved in intracellular signaling, and a novel homolog of H-Ras as well as a novel cytoskeleton- associated protein. We are also characterizing neural delayed early genes (DEGs), which function as late “effector” genes. Based on the functional roles of these “effector” proteins in neural plasticity, we propose a model in which they are directly or indirectly involved in an induction of synaptic restructuring that underlies memory storage.