Laboratory of Developmental Genetics, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
Laboratoire de Physique Statistique, Ecole Normale Supérieure, CNRS, Université Pierre et Marie Curie, Université Paris Diderot, 75005, Paris, France.
Nat Commun. 2019 Apr 23;10(1):1882. doi: 10.1038/s41467-019-09581-4.
Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling. The effects of glutamate spillover on animal behavior and its neural correlates are poorly understood. We developed a glutamate spillover model in Caenorhabditis elegans by inactivating the conserved glial glutamate transporter GLT-1. GLT-1 loss drives aberrant repetitive locomotory reversal behavior through uncontrolled oscillatory release of glutamate onto AVA, a major interneuron governing reversals. Repetitive glutamate release and reversal behavior require the glutamate receptor MGL-2/mGluR5, expressed in RIM and other interneurons presynaptic to AVA. mgl-2 loss blocks oscillations and repetitive behavior; while RIM activation is sufficient to induce repetitive reversals in glt-1 mutants. Repetitive AVA firing and reversals require EGL-30/Gαq, an mGluR5 effector. Our studies reveal that cyclic autocrine presynaptic activation drives repetitive reversals following glutamate spillover. That mammalian GLT1 and mGluR5 are implicated in pathological motor repetition suggests a common mechanism controlling repetitive behaviors.
谷氨酸是一种主要的兴奋性神经递质，突触释放后谷氨酸清除受损会促进溢出，诱导突触外信号。谷氨酸溢出对动物行为及其神经相关性的影响知之甚少。我们通过失活保守的神经胶质谷氨酸转运体 GLT-1 在秀丽隐杆线虫中开发了一种谷氨酸溢出模型。GLT-1 的缺失通过将谷氨酸不受控制地振荡释放到控制反转的主要中间神经元 AVA 上，导致异常的重复运动反转行为。重复的谷氨酸释放和反转行为需要表达在 RIM 和 AVA 前突触的谷氨酸受体 MGL-2/mGluR5。mgl-2 的缺失会阻断振荡和重复行为；而 RIM 的激活足以在 glt-1 突变体中诱导重复反转。重复的 AVA 放电和反转需要 EGL-30/Gαq，这是一种 mGluR5 效应器。我们的研究表明，循环自分泌的突触前激活驱动谷氨酸溢出后的重复反转。哺乳动物 GLT1 和 mGluR5 参与病理性运动重复表明存在控制重复行为的共同机制。
