Neurosciences Graduate Program, University of California, San Diego, La Jolla, California 92093, USA.
J Neurosci. 2011 Jul 6;31(27):9998-10008. doi: 10.1523/JNEUROSCI.5640-10.2011.
Gap junction coupling synchronizes activity among neurons in adult neural circuits, but its role in coordinating activity during development is less known. The developing retina exhibits retinal waves--spontaneous depolarizations that propagate among retinal interneurons and drive retinal ganglion cells (RGCs) to fire correlated bursts of action potentials. During development, two connexin isoforms, connexin 36 (Cx36) and Cx45, are expressed in bipolar cells and RGCs, and therefore provide a potential substrate for coordinating network activity. To determine whether gap junctions contribute to retinal waves, we compared spontaneous activity patterns using calcium imaging, whole-cell recording, and multielectrode array recording in control, single-knock-out (ko) mice lacking Cx45 and double-knock-out (dko) mice lacking both isoforms. Wave frequency, propagation speed, and bias in propagation direction were similar in control, Cx36ko, Cx45ko, and Cx36/45dko retinas. However, the spontaneous firing rate of individual retinal ganglion cells was elevated in Cx45ko retinas, similar to Cx36ko retinas (Hansen et al., 2005; Torborg and Feller, 2005), a phenotype that was more pronounced in Cx36/45dko retinas. As a result, spatial correlations, as assayed by nearest-neighbor correlation and functional connectivity maps, were significantly altered. In addition, Cx36/45dko mice had reduced eye-specific segregation of retinogeniculate afferents. Together, these findings suggest that although Cx36 and Cx45 do not play a role in gross spatial and temporal propagation properties of retinal waves, they strongly modulate the firing pattern of individual RGCs, ensuring strongly correlated firing between nearby RGCs and normal patterning of retinogeniculate projections.
缝隙连接耦联使成年神经回路中的神经元活动同步，但它在协调发育过程中活动的作用知之甚少。发育中的视网膜表现出视网膜波——在视网膜中间神经元之间传播的自发去极化，并驱动视网膜神经节细胞（RGC）发射相关的动作电位爆发。在发育过程中，两种连接蛋白异构体，连接蛋白 36（Cx36）和 Cx45，在双极细胞和 RGC 中表达，因此为协调网络活动提供了潜在的基质。为了确定缝隙连接是否有助于视网膜波，我们使用钙成像、全细胞膜片钳记录和多电极阵列记录比较了在对照、单敲除（ko）缺乏 Cx45 的小鼠、双敲除（dko）缺乏两种异构体的小鼠中自发活动模式。在对照、Cx36ko、Cx45ko 和 Cx36/45dko 视网膜中，波的频率、传播速度和传播方向的偏差相似。然而，单个视网膜神经节细胞的自发放电率在 Cx45ko 视网膜中升高，类似于 Cx36ko 视网膜（Hansen 等人，2005；Torborg 和 Feller，2005），这种表型在 Cx36/45dko 视网膜中更为明显。结果，空间相关性，如通过最近邻相关性和功能连接图来测定，显著改变。此外，Cx36/45dko 小鼠的视网膜神经节细胞传入的眼特异性分离减少。总之，这些发现表明，尽管 Cx36 和 Cx45 不参与视网膜波的总体时空传播特性，但它们强烈调节单个 RGC 的放电模式，确保附近 RGC 之间的强烈相关放电和正常的视网膜神经节投射模式。
