The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition
Open accessAbstract
A heterogeneous population of inhibitory neurons controls the flow of information through a neural circuit. Inhibitory synapses that form on pyramidal neuron dendrites modulate the summation of excitatory synaptic potentials and prevent the generation of dendritic calcium spikes. Precisely timed somatic inhibition limits both the number of action potentials and the time window during which firing can occur. The activity-dependent transcription factor NPAS4 regulates inhibitory synapse number and function in cell culture, but how this transcription factor affects the inhibitory inputs that form on distinct domains of a neuron in vivo was unclear. Here we show that in the mouse hippocampus behaviourally driven expression of NPAS4 coordinates the redistribution of inhibitory synapses made onto a CA1 pyramidal neuron, simultaneously increasing inhibitory synapse number on the cell body while decreasing the number of inhibitory synapses on the apical dendrites. This rearrangement of inhibition is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (Bdnf), which specifically regulates somatic, and not dendritic, inhibition. These findings indicate that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.
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Restoring Npas4 expression ameliorates social and cognitive deficits, GABAergic synaptic impairment, and neuronal hyperexcitability in 16p11dp/+ mice.
“Restoring the expression of Npas4, a key regulator of GABA synapses 135,136, ameliorates the social and cognitive deficits, as well as GABAergic synaptic impairment and neuronal hyperexcitability in 16p11dp/+ mice 134.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [135]
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Cites
Interneurons of the hippocampus
Freund, T. F., & Buzsáki, G. (1998) · Hippocampus · doi:10.1002/(sici)1098-1063(1996)6:4 · Cited by 3,423 · see citing works
Widespread transcription at neuronal activity-regulated enhancers
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 · see citing works
Self-citationA new cellular mechanism for coupling inputs arriving at different cortical layers
Larkum, M. E., Zhu, J. J., & Sakmann, B. (1999) · Nature · doi:10.1038/18686 · Cited by 1,180 · see citing works
Enforcement of Temporal Fidelity in Pyramidal Cells by Somatic Feed-Forward Inhibition
Pouille, F., & Scanziani, M. (2001) · Science · doi:10.1126/science.1060342 · Cited by 1,097 · see citing works
Differences between somatic and dendritic inhibition in the hippocampus
Miles, R., Tóth, K., Gulyás, A. I., Hájos, N., & Freund, T. F. (1996) · Neuron · doi:10.1016/s0896-6273(00)80101-4 · Cited by 942 · see citing works
Defined types of cortical interneurone structure space and spike timing in the hippocampus
Somogyi, P., & Klausberger, T. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2004.078915 · Cited by 927 · see citing works
Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition
Royer, S., Zemelman, B. V., Losonczy, A., Kim, J., Chance, F., Magee, J. C., & Buzsáki, G. (2012) · Nature Neuroscience · doi:10.1038/nn.3077 · Cited by 728 · see citing works
Activity-dependent regulation of inhibitory synapse development by Npas4
Lin, Y., Bloodgood, B. L., Hauser, J. L., Lapan, A. D., Koon, A. C., Kim, T.-K., Hu, L. S., Malik, A. N., & Greenberg, M. E. (2008) · Nature · doi:10.1038/nature07319 · Cited by 639 · see citing works
Self-citationParvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli
Atallah, B. V., Bruns, W., Carandini, M., & Scanziani, M. (2012) · Neuron · doi:10.1016/j.neuron.2011.12.013 · Cited by 612 · see citing works
Activation of specific interneurons improves V1 feature selectivity and visual perception
Lee, S.-H., Kwan, A. C., Zhang, S., Phoumthipphavong, V., Flannery, J. G., Masmanidis, S. C., Taniguchi, H., Huang, Z. J., Zhang, F., Boyden, E. S., et al. (2012) · Nature · doi:10.1038/nature11312 · Cited by 593 · see citing works
Light regulates expression of brain-derived neurotrophic factor mRNA in rat visual cortex.
Castrén, E., Zafra, F., Thoenen, H., & Lindholm, D. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.20.9444 · Cited by 513 · see citing works
Regulation of neuronal input transformations by tunable dendritic inhibition
Lovett-Barron, M., Turi, G. F., Kaifosh, P., Lee, P. H., Bolze, F., Sun, X.-H., Nicoud, J.-F., Zemelman, B. V., Sternson, S. M., & Losonczy, A. (2012) · Nature Neuroscience · doi:10.1038/nn.3024 · Cited by 417 · see citing works
Falkenberg, T., Mohammed, A. K., Henriksson, B. G., Persson, H., Winblad, B. G., & Lindefors, N. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90494-r · Cited by 388 · see citing works
Clustered dynamics of inhibitory synapses and dendritic spines in the adult neocortex.
Chen, J. L., Villa, K. L., Cha, J. W., So, P. T. C., Kubota, Y., & Nedivi, E. (2012) · Neuron · doi:10.1016/j.neuron.2012.02.030 · Cited by 341 · see citing works
Liu, G. (2004) · Nature Neuroscience · doi:10.1038/nn1206 · Cited by 339 · see citing works
Compartmentalization of GABAergic inhibition by dendritic spines
Chiu, C. Q., Lur, G., Morse, T. M., Carnevale, N. T., Ellis-Davies, G. C. R., & Higley, M. J. (2013) · Science · doi:10.1126/science.1234274 · Cited by 307 · see citing works
Npas4 Regulates a Transcriptional Program in CA3 Required for Contextual Memory Formation
Ramamoorthi, K., Fropf, R., Belfort, G. M., Fitzmaurice, H. L., McKinney, R. M., Neve, R. L., Otto, T., & Lin, Y. (2011) · Science · doi:10.1126/science.1208049 · Cited by 295 · see citing works
Marty, S., Wehrlé, R., & Sotelo, C. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-21-08087.2000 · Cited by 237 · see citing works
Elimination of Inhibitory Synapses Is a Major Component of Adult Ocular Dominance Plasticity
van Versendaal, D., Rajendran, R., Saiepour, M. H., Klooster, J., Smit‐Rigter, L. A., Sommeijer, J.-P., Zeeuw, C. I. D., Hofer, S. B., Heimel, J. A., & Levelt, C. N. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.015 · Cited by 187 · see citing works
Upregulation of BDNF mRNA Expression in the Barrel Cortex of Adult Mice after Sensory Stimulation
Rocamora, N., Welker, E., Pascual, M., & Soriano, E. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-14-04411.1996 · Cited by 186 · see citing works
The development of hippocampal interneurons in rodents
Danglot, L., Triller, A., & Marty, S. (2006) · Hippocampus · doi:10.1002/hipo.20225 · Cited by 167 · see citing works
NMDA receptors inhibit synapse unsilencing during brain development
Adesnik, H., Li, G., During, M. J., Pleasure, S. J., & Nicoll, R. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0800946105 · Cited by 161 · see citing works
Brigadski, T., Hartmann, M., & Leßmann, V. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1776-05.2005 · Cited by 142 · see citing works
Pattabiraman, P. P., Tropea, D., Chiaruttini, C., Tongiorgi, E., Cattaneo, A., & Domenici, L. (2005) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2004.11.010 · Cited by 132 · see citing works
Kohara, K., Yasuda, H., Huang, Y. Y., Adachi, N., Sohya, K., & Tsumoto, T. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1943-07.2007 · Cited by 124 · see citing works
Baldelli, P., Hernández-Guijo, J. M., Carabelli, V., & Carbone, E. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4227-04.2005 · Cited by 97 · see citing works
The Neuronal PAS Domain Protein 4 (Npas4) Is Required for New and Reactivated Fear Memories
Ploski, J. E., Monsey, M. S., Nguyen, T., Dileone, R., & Schafe, G. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023760 · Cited by 92 · see citing works
Lein, E. S., & Shatz, C. J. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-04-01470.2000 · Cited by 86 · see citing works
Dean, C., Liu, H., Staudt, T., Stahlberg, M. A., Vingill, S., Bückers, J., Kamin, D., Engelhardt, J., Jackson, M. B., Hell, S. W., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.4515-11.2012 · Cited by 56 · see citing works
Turner, D. (1990) · The Journal of Physiology · doi:10.1113/jphysiol.1990.sp017987 · Cited by 53 · see citing works
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Equalizing excitation-inhibition ratios across visual cortical neurons
Xue, M., Atallah, B. V., & Scanziani, M. (2014) · Nature · doi:10.1038/nature13321 · Cited by 722 · see citing works
Spiegel, I., Mardinly, A. R., Gabel, H. W., Bazinet, J. E., Couch, C. H., Tzeng, C. P., Harmin, D. A., & Greenberg, M. E. (2014) · Cell · doi:10.1016/j.cell.2014.03.058 · Cited by 416 · see citing works
The Regulation of Transcription in Memory Consolidation
Alberini, C. M., & Kandel, E. R. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a021741 · Cited by 362 · see citing works
CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus
Soltesz, I., & Losonczy, A. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0118-0 · Cited by 333 · see citing works
Yan, Z., & Rein, B. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01092-3 · Cited by 300 · see citing works
“Restoring the expression of Npas4, a key regulator of GABA synapses [135, 136], ameliorates the social and cognitive deficits, as well as GABAergic synaptic impairment and neuronal hyperexcitability in 16p11”
BackgroundSensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons
Mardinly, A. R., Spiegel, I., Patrizi, A., Centofante, E., Bazinet, J. E., Tzeng, C. P., Mandel-Brehm, C., Harmin, D. A., Adesnik, H., Fagiolini, M., et al. (2016) · Nature · doi:10.1038/nature17187 · Cited by 176 · see citing works
Marques-Smith, A., Lyngholm, D., Kaufmann, A.-K., Stacey, J. A., Hoerder-Suabedissen, A., Becker, E. B. E., Wilson, M. C., Molnár, Z., & Butt, S. J. B. (2016) · Neuron · doi:10.1016/j.neuron.2016.01.015 · Cited by 173 · see citing works
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Rein, B., & Yan, Z. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.09.001 · Cited by 160 · see citing works
Joint single-cell measurements of nuclear proteins and RNA in vivo
Chung, H., Parkhurst, C. N., Magee, E. M., Phillips, D., Habibi, E., Chen, F., Yeung, B. Z., Waldman, J., Artis, D., & Regev, A. (2021) · Nature Methods · doi:10.1038/s41592-021-01278-1 · Cited by 144 · see citing works
A NPAS4–NuA4 complex couples synaptic activity to DNA repair
Pollina, E. A., Gilliam, D. T., Landau, A. T., Lin, C., Pajarillo, N., Davis, C. P., Harmin, D. A., Yap, E.-L., Vogel, I. R., Griffith, E. C., et al. (2023) · Nature · doi:10.1038/s41586-023-05711-7 · Cited by 125 · see citing works
Self-citationModulation of apoptosis controls inhibitory interneuron number in the cortex
Denaxa, M., Neves, G., Rabinowitz, A., Kemlo, S., Liodis, P., Burrone, J., & Pachnis, V. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.064 · Cited by 112 · see citing works
Joseph, A., & Turrigiano, G. G. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.0618-17.2017 · Cited by 94 · see citing works
Emerging roles for MEF2 in brain development and mental disorders
Assali, A., Harrington, A. J., & Cowan, C. W. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.04.008 · Cited by 92 · see citing works
Synapse rearrangements upon learning: from divergent–sparse connectivity to dedicated sub-circuits
Caroni, P., Chowdhury, A., & Lahr, M. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.08.011 · Cited by 85 · see citing works
Bigio, B., Mathé, A. A., Sousa, V. C., Zelli, D., Svenningsson, P., McEwen, B. S., & Nasca, C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603111113 · Cited by 85 · see citing works
Synapse development organized by neuronal activity-regulated immediate-early genes
Kim, S., Kim, H., & Um, J. W. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0025-1 · Cited by 77 · see citing works
Rein, B., Tan, T., Yang, F., Wang, W., Williams, J., Zhang, F., Mills, A., & Yan, Z. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-0693-9 · Cited by 58 · see citing works
Unno, K., Sumiyoshi, A., Konishi, T., Hayashi, M., Taguchi, K., Muguruma, Y., Inoue, K., Iguchi, K., Nonaka, H., Kawashima, R., et al. (2020) · Nutrients · doi:10.3390/nu12010174 · Cited by 39 · see citing works
Sun, X., Jing, L., Li, F., Zhang, M., Diao, X., Zhuang, J., Rastinejad, F., & Wu, D. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2208804119 · Cited by 32 · see citing works
- Authors
- Bloodgood, B. L., Sharma, N., Browne, H. A., Trepman, A. Z., & Greenberg, M. E.
- Affiliations
- Harvard University (US)
- Corresponding author
- Greenberg, Michael E.
- Venue
- Nature
- Published
- 2013-11
- Volume
- 503
- Issue
- 7474
- Pages
- 121-125
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4169177
- OpenAlex
- W2036442917
- Cited by
- 310
- References
- 30
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 27 · 2023: 17 · 2022: 29 · 2021: 31 · 2020: 19 · 2019: 22 · 2018: 25 · 2017: 26 · 2016: 30 · 2015: 20 · 2014: 20 · 2013: 2
- FWCI
- 11.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS028829, P01NS047572, R01NS028829, P30NS047101, 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 › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- Npas4, brain-derived neurotrophic factor, inhibitory synapses, dendritic inhibition, somatic inhibition, sensory enrichment, hippocampus, CA1 pyramidal neurons, activity-dependent transcription, dendritic plasticity
- MeSH terms
- Animals, Dendrites, Female, Hippocampus, Male, Neural Inhibition, Neuronal Plasticity, Neurons, Synapses, Pyramidal Cells, Mice, Knockout, Brain-Derived Neurotrophic Factor, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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