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.
Highlights
Synaptic integration mechanisms in neurons combine synaptic potentials to control action-potential firing
To understand the computational properties of AGRP neurons, we investigated their synaptic physiology in conjunction with neuronal modeling, cell type-specific RNA sequencing (RNA-seq) data, and gene expression perturbation methods to probe how excitatory synaptic inputs control AGRP neuron firing
We found remarkably efficient synaptic integration properties and determined an underlying molecular mechanism that is found in AGRP neurons and multiple other hypothalamic cell types, is observed in vivo, and is required for normal body weight regulation
Summary
Synaptic integration mechanisms in neurons combine synaptic potentials to control action-potential firing. AGRP neurons in the hypothalamic arcuate nucleus (ARC) regulate appetite and body weight on long timescales ranging from minutes to hours, in part, by integrating hormonal signals (Gao and Horvath, 2007), which includes hormone action on excitatory synaptic inputs (Yang et al, 2011). These neurons undergo marked synaptic plasticity in response to changing metabolic and hormonal states (Liu et al, 2012; Pinto et al, 2004; Yang et al, 2011), indicating an important role for synaptic control over AGRP neuron activity. We found remarkably efficient synaptic integration properties and determined an underlying molecular mechanism that is found in AGRP neurons and multiple other hypothalamic cell types, is observed in vivo, and is required for normal body weight regulation
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