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Npas4 Regulates Excitatory-Inhibitory Balance within Neural Circuits through Cell-Type-Specific Gene Programs

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Spiegel, Ivo, Mardinly, Alan R., Gabel, Harrison W., Bazinet, Jeremy E., Couch, Cameron H., Tzeng, Christopher P., Harmin, David A., Greenberg, Michael E.·2014·Cell

DOI 10.1016/j.cell.2014.03.058PMC PMC4089405

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Abstract

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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Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
A comparison of normalization methods for high density oligonucleotide array data based on variance and bias
Bolstad, B. M., Irizarry, R. A., Åstrand, M., & Speed, T. P. (2003) · Bioinformatics · doi:10.1093/bioinformatics/19.2.185 · Cited by 8,314
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907
Histone H3K27ac separates active from poised enhancers and predicts developmental state
Creyghton, M. P., Cheng, A. W., Welstead, G. G., Kooistra, T., Carey, B. W., Steine, E. J., Hanna, J., Lodato, M. A., Frampton, G. M., Sharp, P. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016071107 · Cited by 4,302
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143
Interneurons of the neocortical inhibitory system
Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1519 · Cited by 2,954 · cited 3×
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Kim, T.-K., Hemberg, M., Gray, J. M., Costa, A. M., Bear, D. M., Wu, J., Harmin, D. A., Laptewicz, M., Barbara-Haley, K., Kuersten, S., et al. (2010) · Nature · doi:10.1038/nature09033 · Cited by 2,450 · cited 2×
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Learning and memory in molecular networks
Lissek, T. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152805 · Cited by 3
Chromatin accessibility landscapes define stromal cell identities across tissues
Nooranikhojasteh, A., Tavallaee, G., Khuu, N., Shen, S. Y., Ouladan, S., Raman, A., & Orouji, E. (2026) · Communications Biology · doi:10.1038/s42003-026-09720-w · Cited by 2
“Npas4 , located on chromosome 19, plays a critical role in neuronal gene expression and synaptic plasticity 35 , with chromatin loops suggesting extensive regulatory interactions.”
Short-term parental exposure to diazepam disrupts development, behavior, and transcriptional profiles in zebrafish offspring
Xu, Q., Xie, Y., Tang, J., Su, Z., Chen, K., Mao, G., Zhao, R.-J., Takai, Y., Shimasaki, Y., & Qiu, X. (2026) · Aquatic Toxicology · doi:10.1016/j.aquatox.2026.107957 · Cited by 2
The Yin and Yang of Arnt2 in Activity-Dependent Transcription
Okur, Z., & Scheiffele, P. (2019) · Neuron · doi:10.1016/j.neuron.2019.04.006 · Cited by 2
Effect of Short-Term Restraint Stress on the Expression of Genes Associated with the Response to Oxidative Stress in the Hypothalamus of Hypertensive ISIAH and Normotensive WAG Rats
Makovka, Y. V., Oshchepkov, D. Y., Fedoseeva, L. A., Markel, А. L., & Redina, O. E. (2024) · Antioxidants · doi:10.3390/antiox13111302 · Cited by 4
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Catching the Brain in the Act
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“IEGs direct programs of late-response gene transcription that are neuronal subtype specific and tailored to the function of each neuron within a neural circuit (Mardinly et al., 2016; Spiegel et al., 2014).”
Background
Intercellular Networks Underlying Developmental Decisions
Chao, M. V. (2016) · Neuron · doi:10.1016/j.neuron.2016.08.025 · Cited by 2
“Efforts have been made to distinguish transcriptional regulators and activity-dependent genes that are specific for inhibitory versus excitatory neurons (Spiegel et al., 2014).”
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Cross-species systems analysis of evolutionary toolkits of neurogenomic response to social challengePreprint
Saul, M. C., Blatti, C., Yang, W., Bukhari, S. A., Shpigler, H. Y., Troy, J. M., Seward, C. H., Sloofman, L., Chandrasekaran, S., Bell, A. M., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/219444 · Cited by 2
Temporal regulation of nicotinic acetylcholine receptor subunits supports central cholinergic synapse developmentPreprint
Rosenthal, J., Yin, J., Long, C., Spillman, E., Sheng, C., & Yuan, Q. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/790659 · Cited by 2
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Shi, J., Nutkovich, B., Kushinsky, D., Rao, B. Y., Herrlinger, S. A., Tsivourakis, E., Mihaila, T. S., Paredes, M. E. C., Malina, K. C.-K., O’Toole, C. K., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.21.586118 · Cited by 2
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Arai, M., Osanai, H., Snell, C. C., 北村, 貴., & Ogawa, S. K. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.21.649441 · Cited by 2
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Yoo, J., Xie, F., Butrus, S., Xu, R., Tan, Z., Gorzek, R. C., Mirshahidi, P., Tring, E., Suresh, S., Kim, J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.22.677893 · Cited by 2
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Dan, S., Turner, M. A., DeBerardine, M., Caceres, L., Nieto-Caballero, V. E., Schembri, J., Levandowski, K. M., Cardenas, C., Wang, N., Li, C., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.22.689869 · Cited by 4
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“Seminal works showed how sensory-driven transcriptional programmes vary between interneuron types to regulate cortical wiring and behaviour, through the immediate early gene (IEG) response to activity changes [37,38].”
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Lukin, J., Beckel, M. S., Pedroncini, O., Giusti, S. A., Mauro, G. C. D., Linenberg, I. M., Patop, I. L., Chernomoretz, A., Marín‐Burgin, A., Kadener, S., et al. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1609772 · Cited by 2
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Ma, X., Zhao, L., Pan, H., Feng, Z., Lin, J., Ji, J., Li, J., Liu, X., Wang, J., Tang, X., et al. (2026) · The Journals of Gerontology Series A · doi:10.1093/gerona/glag022 · Cited by 1
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“Npas4 (Neuronal Per/Arnt/Sim (PAS) domain protein 4) is a member of the helix-loop-helix class of transcriptional regulators involved in numerous developmental events via neuronal activity [24, 25].”
Background
NARP-related alterations in the excitatory and inhibitory circuitry of socially isolated mice: developmental insights and implications for autism spectrum disorder
Yamaguchi, Y., Okamura, K., Yamamuro, K., Okumura, K., Komori, T., Toritsuka, M., Takada, R., Nishihata, Y., Ikawa, D., Yamauchi, T., et al. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1403476 · Cited by 1
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Thompson, J. R., & Lin, Y. (2024) · Springer eBooks · doi:10.1007/978-3-031-68550-7_10 · Cited by 1
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Pruunsild, P., Bengtson, C. P., Yan, J., Bading, H., & Hagenston, A. M. (2024) · Springer eBooks · doi:10.1007/978-3-031-68550-7_4 · Cited by 1
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Ihara, D., Narumoto, A., Kande, Y., Hayashi, T., Ikuno, Y., Shirai, M., Wakabayashi, M., Nitta, R., Naka-Kaneda, H., & Katsuyama, Y. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02640-4 · Cited by 2
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Nagai, T., Shan, W., & Yamada, K. (2019) · YAKUGAKU ZASSHI · doi:10.1248/yakushi.18-00213-4 · Cited by 1
Pulmonary hemodynamic and tidal volume changes during exercise in heart failure.
Agostoni, P., Guazzi, M., Doria, E., & Marenzi, G. (2002) · PubMed · Cited by 1
Dendritic trafficking faces physiologically critical speed-precision tradeoffsPreprint
Williams, A. H., O’Donnell, C., B, T. J. S. A., & O’Leary, T. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/037374 · Cited by 1
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Prestigio, C., Ferrante, D., Marte, A., Romei, A., Lignani, G., Onofri, F., Valente, P., Benfenati, F., & Baldelli, P. (2021) · eLife · doi:10.7554/elife.69058.sa2 · Cited by 1
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Huang, M., Pieraut, S., Cao, J., Polli, F. S., Roncacè, V., Shen, G., & Maximov, A. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.14.496205 · Cited by 1
“Npas4 whose transcription is regulated in cortical INs by visual experience (18, 19) (Fig.”
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“More recently, transcriptome-wide approaches have systematically cataloged genes induced by defined stimulation paradigms 6,7 or by learning-related experiences 8–10 .”
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Background
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Background
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テアニン
Unno, K. (2020) · KAGAKU TO SEIBUTSU · doi:10.1271/kagakutoseibutsu.58.667
Peer Review #1 of "Structural insights and characterization of human Npas4 protein (v0.2)"
(2018) · PeerJ · doi:10.7287/peerj.4978v0.2/reviews/1
Faculty Opinions recommendation of Visual Experience-Dependent Expression of Fn14 Is Required for Retinogeniculate Refinement.
Kano, M., & Watanabe, T. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.733679252.793562681
Peer Review #2 of "Structural insights and characterization of human Npas4 protein (v0.1)"
(2018) · PeerJ · doi:10.7287/peerj.4978v0.1/reviews/2
Faculty Opinions recommendation of HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors.
Dorit Ron, A. (2017) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.731384905.793538334
Peer Review #1 of "Structural insights and characterization of human Npas4 protein (v0.1)"
(2018) · PeerJ · doi:10.7287/peerj.4978v0.1/reviews/1
Determination of Neuron Activation States Facilitated by Artificial Intelligence
Topasna, A., Xie, E., Park, S., Huang, S. W., Wu, X., & Xie, H. (2022) · IEEE International Conference on Bioinformatics and Biomedicine (BIBM) · doi:10.1109/bibm55620.2022.9995647
“Induced by neuronal activity, drastic gene expression changes have been well documented in activated neurons and can be categorized based on the time elapsed [2].”
Background
Reviewer #2 (Public Review): Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons
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Jia, Y., Zhan, J., Huang, P., Li, X., Hong, D., & Lu, X. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47040225
“Spiegel et al. observed that Npas4 selectively upregulates Frmpd3 expression in inhibitory neurons [14].”
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Tao, J., Yang, Y., Guo, Y. X., Zhang, Y., Le, Q., Huang, N., Liu, X., Yu, J., Ma, L., & Wang, F. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.19.654996
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“This, in turn, leads to functional changes in neuronal networks [49] and the shift in neurotransmitter phenotypes, e.g., from cholinergic to GABAergic during learning [50], or from excitatory to inhibitory in spinal interneurons due to SCI [51].”
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“…on the perspective of the investigation, but in general describes the ability of the neuron to keep its overall firing pattern in a narrow range (Eichler and Meier, 2008) applying different regulatory mechanisms of excitatory and inhibitory inputs in the PCs and INs (Spiegel et al., 2014).”
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Deletion of NPAS4 in olfactory bulb principal neurons alters E/I balance and impairs decoding of chemically similar odour molecules
Wolf, D., Oettl, L., Sánchez-Guardado, L. Ó., Linster, C., Lois, C., & Kelsch, W. (2025) · The Journal of Physiology · doi:10.1113/jp288011
“NPAS4 does not increase inhibition globally; it specifically enhances inhibitory input onto active excitatory neurons, allowing for precise homeostatic control for instance through compartment-specific BDNF expression (Bloodgood et al., 2013; Spiegel et al., 2014).”
Additional file 2 of BDNF-TrkB signaling-mediated upregulation of Narp is involved in the antidepressant-like effects of (2R,6R)-hydroxynorketamine in a chronic restraint stress mouse model
Ju, L., Yang, J., Zhu, T., Liu, P., & Yang, J. (2022) · Figshare · doi:10.6084/m9.figshare.19367716
Additional file 3 of BDNF-TrkB signaling-mediated upregulation of Narp is involved in the antidepressant-like effects of (2R,6R)-hydroxynorketamine in a chronic restraint stress mouse model
Ju, L., Yang, J., Zhu, T., Liu, P., & Yang, J. (2022) · Figshare · doi:10.6084/m9.figshare.19367719
Additional file 1 of BDNF-TrkB signaling-mediated upregulation of Narp is involved in the antidepressant-like effects of (2R,6R)-hydroxynorketamine in a chronic restraint stress mouse model
Ju, L., Yang, J., Zhu, T., Liu, P., & Yang, J. (2022) · Figshare · doi:10.6084/m9.figshare.19367713
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Spine nanostructure profiling of cultured neurons from mouse models reveals a schizophrenia-linked role for Ecrg4Preprint
Kashiwagi, Y., Liu, Q., Go, Y., Saito, R., Aiba, A., Nakazawa, T., & Okabe, S. (2025) · eLife · doi:10.7554/elife.109083
“…been previously implicated in the pathology of schizophrenia ( Met ) ( Qiu et al., 2014 ), synaptic plasticity ( Npas4 ) ( Bloodgood et al., 2013 ; Spiegel et al., 2014 ), or signaling pathways in the nervous system ( Arhgap15 , Zamboni et al., 2016 ; Cip4 , Ba et al., 2016 ; and Ecrg4 , Nakatani…”
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Kashiwagi, Y., Liu, Q., Go, Y., Saito, R., Aiba, A., Nakazawa, T., & Okabe, S. (2025) · eLife · doi:10.7554/elife.109083.1
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Bersten, D. C., McDougal, D. P., Sullivan, A. E., Gerassimou, A. G., Breen, J., Fitzsimmons, R. L., Muscat, G. E. O., Pederson, S., Bruning, J. B., Fan, C., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1352 · Cited by 3
“In addition, NPAS4 has been shown to have opposing roles on synapse function and gene regulation in inhibitory versus excitatory neurons [ 86 ].”
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Lin, Q., Kang, C. J., Xavier, A. M., Sanchez-Martin, I., Mehta, A. D., & Cheadle, L. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.18.706645
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Li, L., Mo, B., 程, S. 姗. C., Wei, Z., Yi, M., & Lu, L. (2026) · Chinese Physics B · doi:10.1088/1674-1056/ae4e8c
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Gonzalez, A. E., Ramos, J. D., Anderson, Z., Sewell, C. M., Modaberi, S., Hentges, S. T., Brown, T. E., & Sorg, B. A. (2026) · Neuropharmacology · doi:10.1016/j.neuropharm.2026.110912
“Npas4 promotes excitation onto inhibitory neurons, thereby inhibiting excitatory output (Spiegel et al., 2014), and its expression in the mPFC plays a major role in chronic stress-induced hypofrontality and anhedonia in mice (Hughes et al., 2023).”
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Kawai, A., Suzuki, S., Shigeto, H., Akigawa, S., Ohta, K.-I., Otabi, H., & Miki, T. (2026) · Journal of Neurochemistry · doi:10.1111/jnc.70410
“Furthermore, Npas4, which was enriched in genes upregulated in more mature cultures (3 weeks), is an immediate-early gene known to regulate inhibitory synapse formation and synaptic plasticity in response to activity and BDNF (Lin et al. 2008; Spiegel et al. 2014).”
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“…to be enriched throughout the brain (Ooe et al., 2004; Leong et al., 2013; Choy et al., 2015) and plays an important role in the expression of immediate early response genes such as c-Fos and BDNF participating in synaptic plasticity (Lin et al., 2008; Bloodgood et al., 2013; Spiegel et al., 2014).”
The Unexplored Role of Noncoding Regulatory RNAs in Engram Dynamics
Nanda, P., & Schratt, G. M. (2026) · The Neuroscientist · doi:10.1177/10738584261425960
“During neurode-velopment, Npas4 regulates inhibitory drive onto excitatory neurons while reciprocally strengthening excitatory connectivity (Spiegel et al 2014).”

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.
ORCID: Spiegel, Ivo
Mardinly, Alan R.
Gabel, Harrison W.
Tzeng, Christopher P.
Greenberg, Michael E.
Venue: Cell
Publisher: Elsevier BV
Published: 2014-05
Volume: 157
Issue: 5
Pages: 1216-1229
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2014.03.058
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 414 d)
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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Npas4 Regulates Excitatory-Inhibitory Balance within Neural Circuits through Cell-Type-Specific Gene Programs

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