Near-Perfect Synaptic Integration by Na v 1.7 in Hypothalamic Neurons Regulates Body Weight
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Neurons are well suited for computations on millisecond timescales, but some neuronal circuits set behavioral states over long time periods, such as those involved in energy homeostasis. We found that multiple types of hypothalamic neurons, including those that oppositely regulate body weight, are specialized as near-perfect synaptic integrators that summate inputs over extended timescales. Excitatory postsynaptic potentials (EPSPs) are greatly prolonged, outlasting the neuronal membrane time-constant up to 10-fold. This is due to the voltage-gated sodium channel Nav1.7 (Scn9a), previously associated with pain-sensation but not synaptic integration. Scn9a deletion in AGRP, POMC, or paraventricular hypothalamic neurons reduced EPSP duration, synaptic integration, and altered body weight in mice. In vivo whole-cell recordings in the hypothalamus confirmed near-perfect synaptic integration. These experiments show that integration of synaptic inputs over time by Nav1.7 is critical for body weight regulation and reveal a mechanism for synaptic control of circuits regulating long term homeostatic functions.
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Persistent activity seems to be a hallmark of hypothalamic neurons, which can be highly interconnected and have long integration periods.
“Persistent activity seems to be a hallmark of hypothalamic neurons, which can be highly interconnected and have long integration periods42–45.”
From Neural circuitry for maternal oxytocin release induced by infant cries (2023) · cites this paper as [43]
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References 48 · Cited by 89
- Authors
- Branco, T., Tozer, A., Magnus, C. J., Sugino, K., Tanaka, S., Lee, A. K., Wood, J. N., & Sternson, S. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- MRC Laboratory of Molecular Biology (GB)
- University College London (GB)
- Corresponding author
- Branco, Tiago
- Sternson, Scott M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 165
- Issue
- 7
- Pages
- 1749-1761
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4912688
- OpenAlex
- W2433699362
- Cited by
- 89
- References
- 48
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 11 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 6 · 2019: 13 · 2018: 16 · 2017: 9 · 2016: 6
- FWCI
- 9.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (10154, 101054/Z/13/Z, 098400/Z/12/Z)
- Versus Arthritis (20200)
- Biotechnology and Biological Sciences Research Council (BB/F000227/1)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Nav1.7, SCN9A, voltage-gated sodium channels, synaptic integration, excitatory postsynaptic potentials, hypothalamic neurons, body weight regulation, energy homeostasis, AgRP neurons, POMC neurons, paraventricular hypothalamus
- MeSH terms
- Body Weight Maintenance, Animals, Homeostasis, Hypothalamus, Male, Mice, Transgenic, Neurons, Synapses, Mice, Agouti-Related Protein, NAV1.7 Voltage-Gated Sodium Channel
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