Near-Perfect Synaptic Integration by Na v 1.7 in Hypothalamic Neurons Regulates Body Weight

Abstract

SummaryNeurons 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.

The role of negative conductances in neuronal subthreshold properties and synaptic integration

“…Several approaches have been considered to circumvent this limitation, such as the injection of artificial EPSCs directly into the postsynaptic neuron (Stuart and Sakmann 1995;Ceballos et al 2017), local application of sodium or calcium blockers to the postsynaptic neuron (González-Burgos and Barrionuevo 2001;Stuart and Sakmann 1995) and the use of intracellular sodium channel blockers, such as QX 314 (Deisz et al 1991;González-Burgos and Barrionuevo 2001). Recently, more advanced techniques have been used, such as glutamate uncaging (Carter et al 2012;Liu and Shipley 2008) or knockout animals of Na v channels (Branco et al 2016). Additional strategies, such as canceling the endogenous I NaP or applying an artificial I NaP with dynamic clamp (Ceballos et al 2017;Vervaeke et al 2006), have also been employed to analyze the effects of this conductance on the EPSPs.…”

“…The amplification of EPSPs by I NaP has been extensively observed in neurons from the neocortex (Andreasen and Lambert 1999;Carter et al 2012;Deisz et al 1991;Fricker and Miles 2000;González-Burgos and Barrionuevo 2001;Hirsch and Gilbert 1991;Lipowsky et al 1996;Rotaru et al 2007;Schwindt and Crill 1995;Stafstrom et al 1985;Stuart and Sakmann 1995;Thomson et al 1988;Zsiros and Hestrin 2005), hippocampus (Ceballos et al 2017;Urban et al 1998;Vervaeke et al 2006), entorhinal cortex (Economo et al 2014;Rosenkranz and Johnston 2007), dorsal cochlear nucleus (Hirsch and Oertel 1988), subthalamic nucleus (Farries et al 2010), hypothalamus (Branco et al 2016), olfactory bulb (Liu and Shipley 2008), dorsal horn of the spinal cord (Prescott and De Koninck 2005), medial superior olive and substantia nigra pars compacta (Yamashita and Isa 2004). In most of these experiments, blocking I NaP with TTX abolished the voltage dependence of the EPSP amplitude and area.…”

“…Farries et al (2010) showed in neurons of the subthalamic nucleus that negative slope conductance of I NaP can oppose the positive slope conductance produced by other subthreshold currents, creating a wide region with zero slope conductance which establishes an infinite time constant and strongly reduces the decay phase of EPSPs. Moreover, Branco et al (2016) showed that in hypothalamic neurons, the prolonged EPSPs produced by I NaP are critical for the regulation of body weight.…”

Harveian Oration 2016: Some observations on the causes and consequences of obesity

“…35 It has recently been recognised that hypothalamic neurons concerned with leptin sensing and body weight regulation have particular electrophysiological properties that make them uniquely suited to the integration of incoming hormonal and neural signals over the medium to long term. 36 …”

Slowly Building Excitement

“…Since this is about 10-fold longer than expected from the membrane time constants of these cells, the authors presumed that an active amplification of the excitatory inputs by ion channels was responsible for this EPSP prolongation. Indeed, in acute slice experiments, Branco et al (2016) found that a persistent sodium current, mediated by the alpha subunit 1.7 (Nav1.7/SCN9a), specifically prolonged the excitatory postsynaptic potentials.The key experiment, however, is the in vivo demonstration that hypothalamic PVH neurons can indeed amplify synaptic inputs ''near-perfectly.'' Moreover, without this form of integration, the low input frequencies that are observed in vivo would likely be insufficient to drive any relevant action potential output of these cells.…”