Abstract
Excitation–transcription coupling (E–TC) links synaptic and cellular activity to nuclear gene transcription. It is generally accepted that E–TC makes a crucial contribution to learning and memory through its role in underpinning long-lasting synaptic enhancement in late-phase long-term potentiation and has more recently been linked to late-phase long-term depression: both processes require de novo gene transcription, mRNA translation and protein synthesis. E–TC begins with the activation of glutamate-gated N-methyl-d-aspartate-type receptors and voltage-gated L-type Ca2+ channels at the membrane and culminates in the activation of transcription factors in the nucleus. These receptors and ion channels mediate E–TC through mechanisms that include long-range signalling from the synapse to the nucleus and local interactions within dendritic spines, among other possibilities. Growing experimental evidence links these E–TC mechanisms to late-phase long-term potentiation and learning and memory. These advances in our understanding of the molecular mechanisms of E–TC mean that future efforts can focus on understanding its mesoscale functions and how it regulates neuronal network activity and behaviour in physiological and pathological conditions.
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Acknowledgements
H.M. was supported by the National Natural Science Foundation of China (81930030, 82230036 and 31722023), the Science and Technology Innovation 2030-Major Project (2021ZD0203501), the National Key R&D Program of China (2019YFA0508603), the Project for Hangzhou Medical Disciplines of Excellence and the Key Project for Hangzhou Medical Disciplines. H.G.K. was supported by NIMH (T32MH019524). X.W. was supported by NIGMS (RM1 HG009491 to J.D. Boeke). X.H. was supported by the National Natural Science Foundation of China (32200788). R.W.T. and his associates were supported by NINDS (R01NS125271 and R01NS24067), NIMH (R01MH071739), the Simons Foundation, the Burnett Family Foundation, the Marlene & Paolo Fresco Foundation and the Vulnerable Brain Project. The authors thank B. Li and R.J. Colbran for comments on the manuscript.
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All authors researched data for the article, contributed substantially to discussion of the content and wrote the article. R.W.T., H.M., H.G.K. and X.W. reviewed and/or edited the manuscript before submission.
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Glossary
- Autophosphorylation
-
A process in which a protein kinase catalyses the addition of a phosphate group to specific sites in its own sequence.
- Behavioural timescale plasticity
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(BTSP). A type of synaptic plasticity that integrates neuronal signals over a seconds-long timescale.
- Enhancer
-
A region of DNA that regulates the transcription of genes.
- Immediate early genes
-
A group of genes that are rapidly and transiently activated on neuronal activity.
- Local translation
-
The process of protein synthesis occurring directly within dendrites or axons.
- Long-term potentiation
-
(LTP). A persistent increase in synaptic strength that occurs after stimulation of a specific set of synapses.
- Memory engrams
-
A set of changes in a neuronal network serving as the biological basis for storing memories.
- Morris water maze
-
(MWM). A widely used behavioural test to assess spatial learning and memory, which requires navigation to a submerged platform using spatial cues.
- Plasticity-related proteins
-
Proteins synthesized in association with, and possibly necessary for, synaptic plasticity.
- Postsynaptic density
-
A huge protein complex associated with postsynaptic membranes of excitatory synapses, first identified as an electron-dense region under electron microscopy.
- Transcription factors
-
Proteins that bind to specific DNA sequences and regulate the transcription of genes.
- Voltage-dependent conformational signal
-
Changes in protein structure in response to changes in membrane potential that are read out for downstream signalling.
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Ma, H., Khaled, H.G., Wang, X. et al. Excitation–transcription coupling, neuronal gene expression and synaptic plasticity. Nat. Rev. Neurosci. 24, 672–692 (2023). https://doi.org/10.1038/s41583-023-00742-5
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DOI: https://doi.org/10.1038/s41583-023-00742-5
