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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 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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“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).”
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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).”
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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 60
Turning over DNA methylation in the mind
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“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
“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 58
“…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
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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).”
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“Furthermore, only a fraction of CCK- and PV-expressing neurons induce NPAS4 in response to depolarization (Spiegel et al., 2014).”
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“Once activated, NPAS4 induces neuronal subtype-specific gene programs and cellular responses (Bloodgood et al., 2013; Spiegel et al., 2014).”
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“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
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The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia
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“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 53
“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].”
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Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp
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“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).”
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Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors
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Age-related dysregulation of homeostatic control in neuronal microcircuits
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“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 .”
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“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
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“Activity-dependent NPAS4 has been shown to upregulate both BDNF and Gpr3 expression in cultured excitatory and inhibitory neurons, respectively [45].”
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Withdrawal of BDNF from hippocampal cultures leads to changes in genes involved in synaptic function
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Dendritic trafficking faces physiologically critical speed-precision tradeoffs
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Metadata
- 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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