Synaptic Mechanisms in the Mammalian Retina

我们的工作集中在视网膜内部的特殊突触上。 小鼠视网膜包含46个不同的神经节细胞(RGC)，但对这些细胞类型中兴奋性突触的多样性知之甚少。最近的转录分析表明，不同类型的RGC表达不同的谷氨酸受体亚单位，但这些模式的生理意义尚不清楚(发表的综述中对此进行了一些讨论)。例如，GluA1是AMPA受体的一个亚单位，广泛表达于大脑的其他部位，主要以单一的RGC类型出现。同样，只有有限的视网膜节细胞表达AMPA受体调节蛋白-3。我们的结果表明，在-3基因敲除小鼠中，表达-3的RGC与相同的RGCs相比，表现出不同的AMPA受体动力学。这些差异在光诱发的反应中也很明显。 突触带在视网膜突触中的作用仍然是个谜。我们假设，这些不同的突触前结构通过确保突触前钙通道和囊泡释放位置之间的一致关系来优化模拟信号。我们的实验现在表明，这个假设是错误的，在这些突触的停靠的小泡中存在一系列的释放概率。其他实验表明，这种异质性可能与突触前CAV通道的电压依赖性共同作用，使这种突触能够在更宽的动态范围内工作。 我们对RD10小鼠视网膜色素变性模型的病理活动的研究已经提出了几个关于在这个过程中改变的突触特征以及缓解突触和回路功能障碍的潜在治疗方法的假说。具体地说，我们正在测试红细胞的病理性去极化是否会减少杆状通路中的信号。通过视网膜神经节细胞的记录，我们发现减少RBC去极化可以减少病理振荡行为，而对视觉信号的影响最小。我们已经在体外视网膜电信号(ERG)中证实了这些结果的一些方面，目前正在进行Rod双极细胞的记录，然后再撰写手稿。

Our work focuses on specialized synapses in the inner retina. The mouse retina contains 46 different ganglion cells (RGCs), but very little is known regarding the diversity of excitatory synapses across these cell types. Recent transcriptomic analyses suggest that different RGC types express distinct sets of glutamate receptor subunits, but the physiological implications of these patterns are unknown (some discussion of this appears in the published review). For example, GluA1, an AMPA receptor subunit, expressed widely throughout the rest of the brain, appears primarily in a single RGC type. Similarly, only a limited subset of RGCs express the AMPA receptor modulatory protein -3. Our results indicate that -3-expressing RGCs exhibit distinct AMPA receptor kinetics compared to the same RGCs in -3 knockout mice. These differences are also apparent in light-evoked responses. The role of synaptic ribbons in retinal synapses remains enigmatic. We hypothesize that these distinct presynaptic structures optimize analog signaling by ensuring a consistent relationship between presynaptic calcium channels and vesicle release sites. Our experiments now indicate that this hypothesis is wrong a range of release probabilities exists among the docked vesicles at these synapses. Other experiments suggest that this heterogeneity may work together with the voltage-dependence of presynaptic Cav channels to enable this synapse to work over a wider dynamic range. Our studies of pathological activity in the rd10 mouse model of retinitis pigmentosa have given rise to several hypotheses regarding synaptic features that are altered during this process and potential therapies to alleviate synaptic and circuit dysfunction. Specifically, we are testing whether pathological depolarization of RBCs diminishes signaling in the rod pathway. Recording from retinal ganglion cells, we have found that reducing RBC depolarization can reduce pathological oscillatory behavior with minimal impact on visual signaling. We have confirmed aspects of these results in in vitro electroretinograms (ERGs) and are currently performing recordings from Rod bipolar cells prior to writing a manuscript.