Vroman Rozan, Klaassen Lauw J, Howlett Marcus H C, Cenedese Valentina, Klooster Jan, Sjoerdsma Trijntje, Kamermans Maarten
Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
PLoS Biol. 2014 May 20;12(5):e1001864. doi: 10.1371/journal.pbio.1001864. eCollection 2014 May.
Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms), highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca²⁺ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form of synaptic modulation may be a widespread phenomenon.
神经元计算强烈依赖于抑制性相互作用。一个这样的例子发生在视网膜的第一个突触处，即水平细胞抑制光感受器。这种相互作用产生了双极细胞感受野的中心/周边组织，对对比度增强至关重要。尽管其在视觉中起着至关重要的作用，但其潜在的突触机制几十年来一直困扰着神经科学界。目前有两种相互竞争的假说：一种是电突触机制，另一种是质子介导机制。在这里，我们表明水平细胞通过这两种机制的意外结合反馈到光感受器。第一种是非常快速的电突触机制，没有突触延迟，使其成为已知最快的抑制性突触之一。第二种是相对较慢（τ≈200毫秒）、极具吸引力的机制。它依赖于通过位于水平细胞树突上的泛素蛋白1通道释放ATP，这些树突侵入视锥突触终末。胞外ATP酶NTPDase1将细胞外ATP水解为AMP、磷酸基团和质子。磷酸基团和质子形成一个pKa为7.2的pH缓冲液，使突触间隙中的pH保持相对酸性。这抑制了视锥细胞的Ca²⁺通道，从而减少了视锥细胞释放的谷氨酸。当水平细胞超极化时，泛素蛋白1通道降低其电导，ATP释放减少，pH缓冲液的形成减少。突触间隙中由此产生的碱化会增加视锥细胞谷氨酸的释放。令人惊讶的是，是ATP的水解而不是ATP本身介导了突触调制。我们的结果不仅解决了关于水平细胞到光感受器反馈的长期问题，还展示了一种新的突触调制形式。由于泛素蛋白1通道和胞外ATP酶在神经系统中强烈表达，且泛素蛋白1的功能与突触可塑性有关，我们预计这种新型的突触调制可能是一种普遍现象。
