Neuronal Activity-Regulated Gene Transcription in Synapse Development and Cognitive Function
Open accessAbstract
Activity-dependent plasticity of vertebrate neurons allows the brain to respond to its environment. During brain development, both spontaneous and sensory-driven neural activity are essential for instructively guiding the process of synapse development. These effects of neuronal activity are transduced in part through the concerted regulation of a set of activity-dependent transcription factors that coordinate a program of gene expression required for the formation and maturation of synapses. Here we review the cellular signaling networks that regulate the activity of transcription factors during brain development and discuss the functional roles of specific activity-regulated transcription factors in specific stages of synapse formation, refinement, and maturation. Interestingly, a number of neurodevelopmental disorders have been linked to abnormalities in activity-regulated transcriptional pathways, indicating that these signaling networks are critical for cognitive development and function.
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One module reflecting a neural activity-dependent gene expression program was a notable exception.
“One notable exception was a module that reflects major components of a well-described (40) neural activity-dependent gene expression program, whose disease relationships are refined in the network analysis section below.”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [40]
Several neuronal modules differentiated BD and SCZ from ASD, including geneM21/isoM30, which captures activity-dependent neuronal gene regulation with hubs including early-response genes ARC, EGR1, NPAS4, NR4A1 and late-response genes BDNF, HOMER1.
“Several neuronal modules that distinguish between the disorders differentiate BD and SCZ from ASD, including the module pair geneM21/isoM30 (Fig 5C), which captures known elements of activity-dependent neuronal gene regulation, whose hubs include classic early-response (ARC, EGR1, NPAS4, NR4A1) and late-response genes (BDNF, HOMER1) (40).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [40]
These genes play critical roles in regulating synaptic plasticity and the balance of excitatory and inhibitory synapses.
“These genes play critical roles in regulating synaptic plasticity and the balance of excitatory and inhibitory synapses (40).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [40]
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Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway
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Interneuron cell types are fit to function
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NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD).
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Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes
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Activity-Regulated Transcription: Bridging the Gap between Neural Activity and Behavior
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Self-citationIntrinsic mechanisms of neuronal axon regeneration
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Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex
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Self-citationStructural plasticity upon learning: regulation and functions
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Enhancer RNA Facilitates NELF Release from Immediate Early Genes
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Tet1 Is Critical for Neuronal Activity-Regulated Gene Expression and Memory Extinction
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Different Neuronal Activity Patterns Induce Different Gene Expression Programs
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Nuclear calcium signalling in the regulation of brain function
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Acute mechanisms underlying antibody effects in anti–N‐methyl‐D‐aspartate receptor encephalitis
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Emerging roles for chromatin as a signal integration and storage platform
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Axon–soma communication in neuronal injury
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The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders
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Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications
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Neuronal plasticity and antidepressant actions
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Intellectual disability and autism spectrum disorders: Causal genes and molecular mechanisms
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Neuronal activity modifies the chromatin accessibility landscape in the adult brain
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An epigenetic barrier sets the timing of human neuronal maturation
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Alzheimer’s Disease: From Firing Instability to Homeostasis Network Collapse
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Adaptive regulation of the brain’s antioxidant defences by neurons and astrocytes
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The HD iPSC Consortium, Lim, R. G., Salazar, L. L., Wilton, D. K., King, A. R., Stocksdale, J. T., Sharifabad, D., Lau, A. L., Stevens, B., Reidling, J. C., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4532 · Cited by 221 · see citing works
Somatic APP gene recombination in Alzheimer’s disease and normal neurons
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Early Alzheimer’s disease pathology in human cortex involves transient cell states
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Ion Channels in Development and Cancer
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Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer’s disease mice
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Histone deacetylases in memory and cognition
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Wnt Signaling in the Vertebrate Central Nervous System: From Axon Guidance to Synaptic FunctionPreprint
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Epigenetic mechanisms of major depression: Targeting neuronal plasticity
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LRP8-Reelin-regulated neuronal enhancer signature underlying learning and memory formation
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The neuroimmunology of degeneration and regeneration in the peripheral nervous system
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LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control
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Engineered 3D vascular and neuronal networks in a microfluidic platform
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Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum
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Self-citationThe roles of protein expression in synaptic plasticity and memory consolidation
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Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1
Risher, W. C., Kim, N., Koh, S., Choi, J.-E., Mitev, P., Spence, E. F., Pilaz, L., Wang, D., Feng, G., Silver, D. L., et al. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201802057 · Cited by 158 · see citing works
Autism spectrum disorder: insights into convergent mechanisms from transcriptomics
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Immediate and deferred epigenomic signatures of in vivo neuronal activation in mouse hippocampus
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Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants
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Bading, H. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20161673 · Cited by 156 · see citing works
Huntingtin Is Required for Normal Excitatory Synapse Development in Cortical and Striatal Circuits
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Laminar and Columnar Development of Barrel Cortex Relies on Thalamocortical Neurotransmission
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Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders
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Activity regulates cell death within cortical interneurons through a Calcineurin-dependent mechanism
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A Neuron-Optimized CRISPR/dCas9 Activation System for Robust and Specific Gene Regulation
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Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity
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Widespread Translational Remodeling during Human Neuronal Differentiation
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Modulating effect of cytokines on mechanisms of synaptic plasticity in the brain
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The Role of Epigenetic Mechanisms in the Regulation of Gene Expression in the Nervous System
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Immediate Early Gene c-fos in the Brain: Focus on Glial Cells
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Chromatin remodeling inactivates activity genes and regulates neural coding
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The activity-dependent histone variant H2BE modulates the life span of olfactory neurons
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Development and plasticity of the corpus callosum
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The Neuron Identity Problem: Form Meets Function
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Core and region-enriched networks of behaviorally regulated genes and the singing genome
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Self-citationContributions of DNA Damage to Alzheimer’s Disease
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“DSBs occur in the promoters of several early response genes and contribute to their transcription [65]; early response genes function in learning and memory [67,68] suggesting an association of DSB accumulation with cognitive decline, a major defect in patients with AD.”
BackgroundFrom trans to cis: transcriptional regulatory networks in neocortical development
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DNA double-strand breaks as drivers of neural genomic change, function, and disease
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Assembly of Excitatory Synapses in the Absence of Glutamatergic Neurotransmission
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Human mutations in integrator complex subunits link transcriptome integrity to brain development
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Beyond Molecular Codes: Simple Rules to Wire Complex Brains
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RNA-binding proteins balance brain function in health and disease
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Emerging Roles of Alternative Pre-mRNA Splicing Regulation in Neuronal Development and Function
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Emerging Roles of Long Non-Coding RNAs as Drivers of Brain Evolution
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Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator
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Emerging roles for MEF2 in brain development and mental disorders
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Plasticity of the epigenome during early-life stress
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Functional and structural comparison of visual lateralization in birds – similar but still different
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Mechanisms by which a CACNA1H mutation in epilepsy patients increases seizure susceptibility
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Genome-wide identification of neuronal activity-regulated genes in Drosophila
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Sensory experience remodels genome architecture in neural circuit to drive motor learning
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Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex
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Adar3 Is Involved in Learning and Memory in Mice
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Macromolecular transport in synapse to nucleus communication
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Mechanisms of dietary flavonoid action in neuronal function and neuroinflammation
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Behavior-related gene regulatory networks: A new level of organization in the brain
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Angelman Syndrome: From Mouse Models to Therapy
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A Brief History of Simulation Neuroscience
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- Authors
- West, A. E., & Greenberg, M. E.
- Affiliations
- Duke Medical Center (US)
- Harvard University (US)
- Corresponding author
- Greenberg, M. E.
- Venue
- Cold Spring Harbor Perspectives in Biology
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-05-09
- Volume
- 3
- Issue
- 6
- Pages
- a005744-a005744
- ISSN
- 1943-0264 (ISSN-L)
- PMC
- PMC3098681
- OpenAlex
- W2119137351
- Cited by
- 532
- References
- 201
- Citations by year
- 2026: 31 · 2025: 35 · 2024: 39 · 2023: 19 · 2022: 35 · 2021: 31 · 2020: 27 · 2019: 43 · 2018: 62 · 2017: 54 · 2016: 38 · 2015: 41 · 2014: 28 · 2013: 28 · 2012: 20
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R37NS028829)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- activity-dependent plasticity, synaptic development, synapse maturation, synaptic refinement, transcription factors, brain development, cognitive development, neurodevelopmental disorders
- MeSH terms
- Cognition Disorders, Gene Expression Regulation, Humans, Models, Genetic, Synaptic Transmission, Neuronal Plasticity, Neurons, Synapses, Transcription Factors, Neurites, Calcium Signaling
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