Transcription control pathways decode patterned synaptic inputs into diverse mRNA expression profiles.
Synaptic plasticity requires transcription and translation to establish long-term changes that form the basis for long term memory. Diverse stimuli, such as synaptic activity and growth factors, trigger synthesis of mRNA to regulate changes at the synapse. The palette of possible mRNAs is vast, and a key question is how the cell selects which mRNAs to synthesize. To address this molecular decision-making, we have developed a biochemically detailed model of synaptic-activity triggered mRNA synthesis. We find that there are distinct time-courses and amplitudes of different branches of the mRNA regulatory signaling pathways, which carry out pattern-selective combinatorial decoding of stimulus patterns into distinct mRNA subtypes. Distinct, simultaneously arriving input patterns that impinge on the transcriptional control network interact nonlinearly to generate novel mRNA combinations. Our model combines major regulatory pathways and their interactions connecting synaptic input to mRNA synthesis. We parameterized and validated the model by incorporating data from multiple published experiments. The model replicates outcomes of knockout experiments. We suggest that the pattern-selectivity mechanisms analyzed in this model may act in many cell types to confer the capability to decode temporal patterns into combinatorial mRNA expression.
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India; Manipal University, Manipal, India.
Pragati
P
Jain
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.
Upinder S
US
Bhalla
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D030541:Databases, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D017476:Receptors, Neuropeptide Y; C109491:neuropeptide Y4 receptor; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium