Near-Perfect Synaptic Integration by Nav1.7 in Hypothalamic Neurons Regulates Body Weight.
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.
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA; Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address: tbranco@mrc-lmb.cam.ac.uk.
Tiago
T
Branco
Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Adam
A
Tozer
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
Christopher J
CJ
Magnus
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
Ken
K
Sugino
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
Shinsuke
S
Tanaka
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
Albert K
AK
Lee
Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
John N
JN
Wood
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA. Electronic address: sternsons@janelia.hhmi.org.
Scott M
SM
Sternson
D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D000068959:Body Weight Maintenance; D006706:Homeostasis; D007031:Hypothalamus / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D013569:Synapses
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D062556:NAV1.7 Voltage-Gated Sodium Channel; C503479:Scn9a protein, mouse