Branco Tiago, Tozer Adam, Magnus Christopher J, Sugino Ken, Tanaka Shinsuke, Lee Albert K, Wood John N, Sternson Scott M
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.
Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Cell. 2016 Jun 16;165(7):1749-1761. doi: 10.1016/j.cell.2016.05.019.
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.
神经元非常适合在毫秒级时间尺度上进行计算，但有些神经回路会在很长一段时间内设定行为状态，比如那些参与能量平衡调节的神经回路。我们发现，多种类型的下丘脑神经元，包括那些对体重起相反调节作用的神经元，都特化为近乎完美的突触整合器，能在较长时间尺度上对输入进行累加。兴奋性突触后电位（EPSP）被极大地延长，其持续时间比神经元膜时间常数长10倍。这是由于电压门控钠通道Nav1.7（Scn9a），该通道此前被认为与痛觉有关，而与突触整合无关。在促肾上腺皮质激素释放肽（AGRP）、促黑素细胞激素（POMC）或下丘脑室旁核神经元中敲除Scn9a会缩短小鼠的EPSP持续时间、减少突触整合并改变体重。下丘脑的体内全细胞记录证实了近乎完美的突触整合。这些实验表明，Nav1.7对突触输入随时间的整合对体重调节至关重要，并揭示了一种对调节长期稳态功能的神经回路进行突触控制的机制。
