Signaling logic of activity-triggered dendritic protein synthesis: an mTOR gate but not a feedback switch

• Published in: PLoS computational biology Vol. 5; no. 2; p. e1000287
• Main Authors: Jain, Pragati, Bhalla, Upinder S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2009; Public Library of Science (PLoS)
• Subjects: Animals; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Calcium - metabolism; Cellular signal transduction; Chemical reactions; Computational biology; Computational Biology/Computational Neuroscience; Computational Biology/Signaling Networks; Computational Biology/Systems Biology; Dendrites; Dendrites - metabolism; Feedback; Genetic aspects; Kinases; Machinery; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases - metabolism; Nerve Tissue Proteins - biosynthesis; Neuroscience/Neural Homeostasis; Neuroscience/Neuronal Signaling Mechanisms; Physiological aspects; Protein biosynthesis; Protein Kinases - metabolism; Protein synthesis; Proteins; Sensitivity analysis; Signal Transduction; TOR Serine-Threonine Kinases; India; Mitogen-Activated Protein Kinases; Animals; Calcium; Protein Kinases; Signal Transduction; Brain-Derived Neurotrophic Factor; Dendrites; Mice; Nerve Tissue Proteins; TOR Serine-Threonine Kinases; Mice, Knockout
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1000287

Changes in synaptic efficacy are believed to form the cellular basis for memory. Protein synthesis in dendrites is needed to consolidate long-term synaptic changes. Many signals converge to regulate dendritic protein synthesis, including synaptic and cellular activity, and growth factors. The coordination of these multiple inputs is especially intriguing because the synthetic and control pathways themselves are among the synthesized proteins. We have modeled this system to study its molecular logic and to understand how runaway feedback is avoided. We show that growth factors such as brain-derived neurotrophic factor (BDNF) gate activity-triggered protein synthesis via mammalian target of rapamycin (mTOR). We also show that bistability is unlikely to arise from the major protein synthesis pathways in our model, even though these include several positive feedback loops. We propose that these gating and stability properties may serve to suppress runaway activation of the pathway, while preserving the key role of responsiveness to multiple sources of input.