Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs
Open accessAbstract
The nervous system adapts to experience by inducing a transcriptional program that controls important aspects of synaptic plasticity. Although the molecular mechanisms of experience-dependent plasticity are well characterized in excitatory neurons, the mechanisms that regulate this process in inhibitory neurons are only poorly understood. Here, we describe a transcriptional program that is induced by neuronal activity in inhibitory neurons. We find that, while neuronal activity induces expression of early-response transcription factors such as Npas4 in both excitatory and inhibitory neurons, Npas4 activates distinct programs of late-response genes in inhibitory and excitatory neurons. These late-response genes differentially regulate synaptic input to these two types of neurons, promoting inhibition onto excitatory neurons while inducing excitation onto inhibitory neurons. These findings suggest that the functional outcomes of activity-induced transcriptional responses are adapted in a cell-type-specific manner to achieve a circuit-wide homeostatic response.
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Npas4 regulates excitatory synapse formation through a transcriptional program in SST+ interneurons involving synaptic scaffolding proteins and Kv1.1.
“Npas4 regulates excitatory synapse formation through the induction of a transcriptional program in SST+ interneurons that involves the expression of several synaptic scaffolding proteins and the shaker-like potassium channel Kv1.1 (Spiegel et al., 2014).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Spiegel et al., 2014
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“However, while activity dependent NPTX2 expression has recently been demonstrated in somatostatin interneurons (Spiegel et al., 2014), NPTX expression has not yet been localized within PVFIs.”
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“control memory-related plasticity also in SST+ INs by altering input and output connectivity in this IN type (Spiegel et al., 2014).”
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“Neuronal activity–coupled gene expression provides one obvious source (Hong et al. 2008, Mardinly et al. 2016, Spiegel et al. 2014; reviewed in Wamsley & Fishell 2017) but could be complemented by similar mechanisms that direct cell type–specific translation, localization, or splicing.”
BackgroundTuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch
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Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency
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A robust activity marking system for exploring active neuronal ensembles
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BackgroundMethodRegulation of Neuronal Differentiation, Function, and Plasticity by Alternative Splicing
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“, elicited by a behavioral stimulus (Ebert and Greenberg, 2013; Nonaka et al., 2014; Spiegel et al., 2014).”
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Evolution of Osteocrin as an activity-regulated factor in the primate brain
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Joint single-cell measurements of nuclear proteins and RNA in vivo
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Genetic strategies to access activated neurons
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Fate and freedom in developing neocortical circuits
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Chromatin remodeling inactivates activity genes and regulates neural coding
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“For instance, recent work indicated that electrical activity influences the migration of post-mitotic interneurons (Bortone and Polleux, 2009; De Marco García et al., 2011), their morphological development, and their connectivity (Spiegel et al., 2014).”
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Core and region-enriched networks of behaviorally regulated genes and the singing genome
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The Epigenome in Neurodevelopmental Disorders
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“Modulation of specific activity-regulated genes can strongly influence circuit function, as seen with Npas4 in synaptic plasticity (Spiegel et al., 2014), parvalbumin (PV) in experience-dependent learning (Donato et al., 2013), and GAD67 in inhibitory synaptic homeostasis (Kinney et al., 2006; Lau…”
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“This is further emphasized by the heterogeneity of neocortical GABAergic cell types and their targets (Tremblay et al., 2016), and emerging evidence that the transcriptional pathways that homeostatically regulate inhibition are cell-type-specific (Bloodgood et al., 2013; Spiegel et al., 2014).”
BackgroundSubstantial DNA methylation differences between two major neuronal subtypes in human brain
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“In line with our hypothesis, it has been shown that significantly more early-(50 versus 28) and late-(808 versus 438) response transcripts were activated in cortical excitatory compared to MGE-derived inhibitory GABA neurons (80).”
Keeping Your Brain in Balance: Homeostatic Regulation of Network Function
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Neurobiological functions of transcriptional enhancers
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Genomic landscape of drug response reveals mediators of anthelmintic resistance
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“Npas4 has previously been shown to engage different downstream transcriptional targets in different cell types and brain regions to modify synaptic connections (Bloodgood et al., 2013; Lin et al., 2008; Sim et al., 2013; Spiegel et al., 2014; Yoshihara et al., 2014).”
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The balancing act of GABAergic synapse organizers
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Synapse rearrangements upon learning: from divergent–sparse connectivity to dedicated sub-circuits
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Signatures of sex: Sex differences in gene expression in the vertebrate brain
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“Conventionally used as histological markers for neural activity, these IEGs are themselves TFs and activate unique repertoires of late response genes (LRGs) in distinct cell types (Hrvatin et al., 2018; Spiegel et al., 2014; Tyssowski et al., 2018).”
BackgroundGenome-wide identification of neuronal activity-regulated genes in Drosophila
Chen, X., Rahman, R., Guo, F., & Rosbash, M. (2016) · eLife · doi:10.7554/elife.19942 · Cited by 91 · see citing works
“Mammalian IEGs are largely shared between different types of neurons such as excitatory and inhibitory neurons (Spiegel et al., 2014), but fly ARGs like SRGs appear quite tissue-type specific, i.e., many genes are only induced in one of the tissue types tested despite similar baseline levels…”
BackgroundInfluentialExcitation–transcription coupling, neuronal gene expression and synaptic plasticity
Ma, H., Khaled, H. G., Wang, X., Mandelberg, N. J., Cohen, S. M., He, X., & Tsien, R. W. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-023-00742-5 · Cited by 83 · see citing works
“NPAS4 activity is involved in plasticity of both excitatory and inhibitory synapses 219,220 and in the formation of long-term memory 218 and motor learning 221 .”
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“…were correspondingly regulated in mouse primary neurons in this study and/or have been shown previously to be activity regulated (Balik et al., 2013; Kim et al., 2010; Maze et al., 2015; Mo et al., 2015; Saha et al., 2011; Spiegel et al., 2014; Zanzouri et al., 2006; Zhang et al., 2007, 2009).”
BackgroundInfluentialChevée, M., Robertson, J. D., Cannon, G. H., Brown, S. P., & Goff, L. A. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.046 · Cited by 76 · see citing works
“…studies showed that averaged responses induced by neural activity measured over hours compared across brain regions or between inhibitory and excitatory neurons exhibit common early transcriptional responses leading to cell-type specific late responses (Spiegel et al., 2014; Whitney et al., 2014).”
Synapse development organized by neuronal activity-regulated immediate-early genes
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Neural Stimulation and Molecular Mechanisms of Plasticity and Regeneration: A Review
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“In some cases, IEG responses mediate transcriptional factors, including growth arrest and DNA damage inducible β (Gadd45β), Npas4, early growth response 4 (Egr4), nuclear receptor subfamily 4 group a member 1 (Nr4a1), Fos, and many others (Spiegel et al., 2014).”
BackgroundAdult Deletion of SRF Increases Epileptogenesis and Decreases Activity-Induced Gene Expression
Kuźniewska, B., Nader, K., Dąbrowski, M., Kaczmarek, L., & Kalita, K. B. (2015) · Molecular Neurobiology · doi:10.1007/s12035-014-9089-7 · Cited by 74 · see citing works
“which is an activity-dependent TF that controls inhibitory synapse development and a number of γ-aminobutyric acid-releasing synapses on excitatory neurons [58, 59]; Bdnf,”
BackgroundHwang, H.-W., Saito, Y., Park, C. Y., Blachère, N. E., Tajima, Y., Fak, J. J., Zucker-Scharff, I., & Darnell, R. B. (2017) · Neuron · doi:10.1016/j.neuron.2017.08.024 · Cited by 74 · see citing works
What Is Excitation/Inhibition and How Is It Regulated? A Case of the Elephant and the Wisemen
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Transcriptomic mapping uncovers Purkinje neuron plasticity driving learning
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Shaping inhibition: activity dependent structural plasticity of GABAergic synapses
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“Although Npas4 has been shown to control numerous genetic pathways that regulate both excitatory and inhibitory synapse function (Spiegel et al., 2014), its role in contextual memory formation could be at least in part mediated by an activity dependent remodeling of GABAergic synapses.”
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Fu, J., Guo, O., Zhen, Z., & Zhen, J. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.603373 · Cited by 72 · see citing works
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RETRACTED: Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers
Brigidi, G. S., Hayes, M. G. B., Santos, N. P. D., Hartzell, A. L., Texari, L., Lin, P.-A., Bartlett, A., Ecker, J. R., Benner, C. W., Heinz, S., et al. (2019) · Cell · doi:10.1016/j.cell.2019.09.004 · Cited by 68 · see citing works
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MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons
Silva, M. M., Rodrigues, B., Fernandes, J., Santos, S. D., Carreto, L. C., Santos, M. A. S., Pinheiro, P. S., & Carvalho, A. L. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1900338116 · Cited by 62 · see citing works
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“Some genes remain upregulated throughout the study, such as Npas4, responsible for regulating excitatory-inhibitory balance (Spiegel et al., 2014).”
BackgroundVisual Experience-Dependent Expression of Fn14 Is Required for Retinogeniculate Refinement
Cheadle, L., Tzeng, C. P., Kalish, B. T., Harmin, D. A., Rivera, S. A., Ling, E., Nagy, M. A., Hrvatin, S., Hu, L. S., Stroud, H., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.036 · Cited by 59 · see citing works
Turning over DNA methylation in the mind
Lister, R., & Mukamel, E. A. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00252 · Cited by 60 · see citing works
“Both excitatory and inhibitory neurons respond to neural activity by expressing common earlyresponse transcription factors, such asNpas4, yet the downstream consequences are highly cell type-specific (Spiegel et al., 2014).”
BackgroundMolecular mechanisms of synaptogenesis
Qi, C., Luo, L.-D., Feng, I., & Ma, S. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.939793 · Cited by 54 · see citing works
“At the transcriptional level, transcription factor NPAS4 can maintain the overall activity at a proper level by promoting the transcription of Bdnf, thus leading to the formation of inhibitory synapses at somatic regions in excitatory neurons, and excitatory synapses in inhibitory neurons (Lin et al., 2008; Bloodgood…”
BackgroundControl of neuronal excitation–inhibition balance by BMP–SMAD1 signalling
Okur, Z., Schlauri, N., Bitsikas, V., Panopoulou, M., Ortiz, R., Schwaiger, M., Karmakar, K., Schreiner, D., & Scheiffele, P. (2024) · Nature · doi:10.1038/s41586-024-07317-z · Cited by 56 · see citing works
“…happen at various timescales, from near instantaneous adjustments of excitation and inhibition during sensory processing 45 , to slower modifications of synaptic connectivity after longer-term shifts in circuit activation as they occur during sensory deprivation but also in disease states 3–5, 15”
Synaptic architecture of a memory engram in the mouse hippocampus
Uytiepo, M., Zhu, Y., Bushong, E. A., Chou, K., Polli, F. S., Zhao, E., Keun-young Kim, A., Luu, D., Chang, L., Yang, D. U., et al. (2025) · Science · doi:10.1126/science.ado8316 · Cited by 54 · see citing works
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“Gain- and loss-of-function approaches have identified 300 downstream target genes of NPAS4 representing a substantial leverage and in parallel diversification potential of stress responses (Lin et al., 2008; Kim et al., 2010; Bloodgood et al., 2013; Spiegel et al., 2014).”
BackgroundInfluentialZhu, Y., Huang, M., Bushong, E. A., Phan, S., Uytiepo, M., Beutter, E., Boemer, D., Tsui, K. C., Ellisman, M. H., & Maximov, A. (2019) · Nature Communications · doi:10.1038/s41467-019-11409-0 · Cited by 53 · see citing works
Hartzell, A. L., Martyniuk, K. M., Brigidi, G. S., Heinz, D. A., Djaja, N. A., Payne, A., & Bloodgood, B. L. (2018) · eLife · doi:10.7554/elife.35927 · Cited by 57 · see citing works
“Furthermore, only a fraction of CCK- and PV-expressing neurons induce NPAS4 in response to depolarization (Spiegel et al., 2014).”
BackgroundSharma, N., Pollina, E. A., Nagy, M. A., Yap, E.-L., DiBiase, F. A., Hrvatin, S., Hu, L. S., Lin, C., & Greenberg, M. E. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.007 · Cited by 50 · see citing works
“Once activated, NPAS4 induces neuronal subtype-specific gene programs and cellular responses (Bloodgood et al., 2013; Spiegel et al., 2014).”
BackgroundClarke, D., Beros, J. L., Bates, K. A., Harvey, A. R., Tang, A. D., & Rodger, J. (2020) · Brain stimulation · doi:10.1016/j.brs.2020.12.007 · Cited by 51 · see citing works
“These fluctuations over time likely reflect a dynamic response to the immediate gene expression changes induced by stimulation, as has been shown in cultured inhibitory and excitatory neurons following KCl depolarisation [48].”
BackgroundAltered Markers of Cortical γ-Aminobutyric Acid Neuronal Activity in Schizophrenia
Kimoto, S., Zaki, M. M., Bazmi, H. H., & Lewis, D. A. (2015) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2015.0533 · Cited by 51 · see citing works
The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia
Choy, F. C., Klarić, T., Koblar, S. A., & Lewis, M. D. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161226144 · Cited by 51 · see citing works
“It has been stated that Npas4 is predominantly expressed in excitatory neurons [7], though subsequent studies have revealed that Npas4 can also be detected in γ-aminobutyric acid (GABA)ergic inhibitory medium spiny neurons in the limbic striatum [21], somatostatin (SST)-expressing interneurons in the medial ganglionic…”
BackgroundMolecular diversity underlying cortical excitatory and inhibitory synapse development
Favuzzi, E., & Rico, B. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.03.011 · Cited by 51 · see citing works
“For example, the activity-dependent transcription factor Npas4 activates distinct programs of late-response genes in different neurons to selectively regulate their excitatory or inhibitory inputs [54 ,55].”
Le, A. A., Lauterborn, J. C., Jia, Y., Wang, W., Cox, C. D., Gall, C. M., & LYNCH, G. S. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-01001-5 · Cited by 48 · see citing works
Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp
Mariga, A., Glaser, J., Mathias, L., Xu, D., Xiao, M., Worley, P., Ninan, I., & Chao, M. V. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.064 · Cited by 45 · see citing works
“There are hints that Narp and BDNF expression are related from microarray analyses of different environmental and developmental states (Tong et al., 2001; Wibrand et al., 2006; Spiegel et al., 2014).”
Plant Species of Sub-Family Valerianaceae—A Review on Its Effect on the Central Nervous System
Das, G., Shin, H., Tundis, R., Gonçalves, S., Tantengco, O. A. G., Campos, M. G., Acquaviva, R., Malfa, G. A., Romano, A., Robles, J. A. H., et al. (2021) · Plants · doi:10.3390/plants10050846 · Cited by 48 · see citing works
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Lineage divergence of activity-driven transcription and evolution of cognitive ability
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Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors
Funahashi, Y., Ariza, A., Emi, R., Xu, Y., Shan, W., Suzuki, K., Kozawa, S., Ahammad, R. U., Wu, M., Takano, T., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.116 · Cited by 45 · see citing works
Age-related dysregulation of homeostatic control in neuronal microcircuits
Radulescu, C. I., Doostdar, N., Zabouri, N., Melgosa-Ecenarro, L., Wang, X., Sadeh, S., Pavlidi, P., Airey, J., Kopanitsa, M. V., Claudia Clopath, A., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01451-z · Cited by 45 · see citing works
“Brain-derived neurotrophic factor signaling is driven by activity-dependent transcription factors, such as Npas4 , which coordinate E:I balance and decline with age 60,61 .”
BackgroundTorres-Hernández, B. A., Colón-Cruz, L., Rosa-Falero, C., Torrado, A. I., Miscalichi, N., Ortíz, J. G., González‐Sepúlveda, L., Pérez-Ríos, N., Suárez-Pérez, E. L., Bradsher, J., et al. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4304-z · Cited by 45 · see citing works
“Technical triplicates with three biological samples of all the different treatments were evaluated for each gene.”
MethodA long noncoding eRNA forms R-loops to shape emotional experience–induced behavioral adaptation
Akiki, R. M., Cornbrooks, R. G., Magami, K., Greige, A., Snyder, K. K., Wood, D. J., Herrington, C. M., Mace, P., Blidy, K., Koike, N., et al. (2024) · Science · doi:10.1126/science.adp1562 · Cited by 47 · see citing works
Kusko, R. L., Dreymann, J., Ross, J., Cha, Y., Escalante-Chong, R., Garcia‐Miralles, M., Tan, L. J., Burczynski, M. E., Zeskind, B., Laifenfeld, D., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0259-3 · Cited by 44 · see citing works
“Activity-dependent NPAS4 has been shown to upregulate both BDNF and Gpr3 expression in cultured excitatory and inhibitory neurons, respectively [45].”
BackgroundMarchisella, F., Creutzberg, K. C., Begni, V., Sanson, A., Wearick‐Silva, L. E., Tractenberg, S. G., Orso, R., Kestering-Ferreira, É., Grassi‐Oliveira, R., & Riva, M. A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.653384 · Cited by 45 · see citing works
Brault, V., Nguyen, T. L., Gutiérrez, J. F., Iacono, G. L., Birling, M., Lalanne, V., Méziane, H., Manousopoulou, A., Pavlovic, G., Lindner, L., et al. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009777 · Cited by 41 · see citing works
Withdrawal of BDNF from hippocampal cultures leads to changes in genes involved in synaptic function
Mariga, A., Zavadil, J., Ginsberg, S. D., & Chao, M. V. (2014) · Developmental Neurobiology · doi:10.1002/dneu.22216 · Cited by 43 · see citing works
Dendritic trafficking faces physiologically critical speed-precision tradeoffs
Williams, A. H., O’Donnell, C., B, T. J. S. A., & O’Leary, T. (2016) · eLife · doi:10.7554/elife.20556 · Cited by 43 · see citing works
- Authors
- Spiegel, I., Mardinly, A. R., Gabel, H. W., Bazinet, J. E., Couch, C. H., Tzeng, C. P., Harmin, D. A., & Greenberg, M. E.
- Affiliations
- Harvard University (US)
- Corresponding author
- Greenberg, Michael E.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 157
- Issue
- 5
- Pages
- 1216-1229
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4089405
- OpenAlex
- W2079540311
- Cited by
- 416
- References
- 52
- Citations by year
- 2026: 31 · 2025: 49 · 2024: 41 · 2023: 28 · 2022: 38 · 2021: 37 · 2020: 29 · 2019: 34 · 2018: 31 · 2017: 32 · 2016: 34 · 2015: 23 · 2014: 8
- FWCI
- 14.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ns048276-15)
- National Institute of Mental Health (T32MH020017)
- National Institute of Neurological Disorders and Stroke (R01NS028829, NS048276, R37NS028829)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- Npas4, excitation-inhibition balance, inhibitory neurons, excitatory neurons, activity-dependent transcription, synaptic plasticity, homeostatic regulation, neural circuits
- MeSH terms
- Animals, Embryo, Mammalian, Gene Expression Regulation, Neurons, Synapses, Transcription, Genetic, Mice, Knockout, Cell Culture Techniques, Mice, Basic Helix-Loop-Helix Proteins
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