Neuronal enhancers fine-tune adaptive circuit plasticity

• Published in: Neuron (Cambridge, Mass.) Vol. 112; no. 18; pp. 3043 - 3057
• Main Authors: Griffith, Eric C., West, Anne E., Greenberg, Michael E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.09.2024
• Subjects: Animals; Brain - physiology; circuit plasticity; enhancer; Enhancer Elements, Genetic - genetics; Gene Expression Regulation; gene regulation; Humans; metaplasticity; Nerve Net - physiology; neuronal activity; Neuronal Plasticity - physiology; Neurons - physiology; transcriptional memory; circuit plasticity; enhancer; transcriptional memory; gene regulation; metaplasticity; neuronal activity
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2024.08.002

Neuronal activity-regulated gene expression plays a crucial role in sculpting neural circuits that underpin adaptive brain function. Transcriptional enhancers are now recognized as key components of gene regulation that orchestrate spatiotemporally precise patterns of gene transcription. We propose that the dynamics of enhancer activation uniquely position these genomic elements to finely tune activity-dependent cellular plasticity. Enhancer specificity and modularity can be exploited to gain selective genetic access to specific cell states, and the precise modulation of target gene expression within restricted cellular contexts enabled by targeted enhancer manipulation allows for fine-grained evaluation of gene function. Mounting evidence also suggests that enduring stimulus-induced changes in enhancer states can modify target gene activation upon restimulation, thereby contributing to a form of cell-wide metaplasticity. We advocate for focused exploration of activity-dependent enhancer function to gain new insight into the mechanisms underlying brain plasticity and cognitive dysfunction. Neuronal activity-responsive gene expression regulates neural circuit plasticity. Griffith et al. review the critical role of cis-regulatory enhancer elements in orchestrating gene expression programs and highlight the promise of enhancer-focused studies to advance understanding of neural plasticity mechanisms.