Suzuki A, Lee L-J, Hayashi Y, Muglia L, Itohara S, Erzurumlu R S, Iwasato T
Division of Neurogenetics, National Institute of Genetics (NIG), Mishima, Shizuoka 411-8540, Japan; Department of Genetics, The Graduate University for Advanced Studies (SOKENDAI), Mishima, Shizuoka 411-8540, Japan.
Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan.
Neuroscience. 2015 Apr 2;290:518-29. doi: 10.1016/j.neuroscience.2015.01.043. Epub 2015 Jan 30.
Cyclic AMP signaling is critical for activity-dependent refinement of neuronal circuits. Global disruption of adenylyl cyclase 1 (AC1), the major calcium/calmodulin-stimulated adenylyl cyclase in the brain, impairs formation of whisker-related discrete neural modules (the barrels) in cortical layer 4 in mice. Since AC1 is expressed both in the thalamus and the neocortex, the question of whether pre- or postsynaptic (or both) AC1 plays a role in barrel formation has emerged. Previously, we generated cortex-specific AC1 knockout (Cx-AC1KO) mice and found that these animals develop histologically normal barrels, suggesting a potentially more prominent role for thalamic AC1 in barrel formation. To determine this, we generated three new lines of mice: one in which AC1 is disrupted in nearly half of the thalamic ventrobasal nucleus cells in addition to the cortical excitatory neurons (Cx/pTh-AC1KO mouse), and another in which AC1 is disrupted in the thalamus but not in the cortex or brainstem nuclei of the somatosensory system (Th-AC1KO mouse). Cx/pTh-AC1KO mice show severe deficits in barrel formation. Th-AC1KO mice show even more severe disruption in barrel patterning. In these two lines, single thalamocortical (TC) axon labeling revealed a larger lateral extent of TC axons in layer 4 compared to controls. In the third line, all calcium-stimulated adenylyl cyclases (both AC1 and AC8) are deleted in cortical excitatory neurons. These mice have normal barrels. Taken together, these results indicate that thalamic AC1 plays a major role in patterning and refinement of the mouse TC circuitry.
环磷酸腺苷（cAMP）信号传导对于神经元回路的活动依赖性精细化至关重要。腺苷酸环化酶1（AC1）是大脑中主要的钙/钙调蛋白刺激型腺苷酸环化酶，其整体功能破坏会损害小鼠皮质第4层中与触须相关的离散神经模块（桶状结构）的形成。由于AC1在丘脑和新皮质中均有表达，因此突触前或突触后（或两者）的AC1是否在桶状结构形成中起作用的问题便出现了。此前，我们构建了皮质特异性AC1基因敲除（Cx-AC1KO）小鼠，并发现这些动物形成了组织学上正常的桶状结构，这表明丘脑AC1在桶状结构形成中可能发挥更突出的作用。为了确定这一点，我们构建了三个新的小鼠品系：一个品系中，除了皮质兴奋性神经元外，丘脑腹侧基底核近一半的细胞中的AC1功能被破坏（Cx/pTh-AC1KO小鼠）；另一个品系中，AC1在丘脑中被破坏，但在体感系统的皮质或脑干核中未被破坏（Th-AC1KO小鼠）。Cx/pTh-AC1KO小鼠在桶状结构形成方面表现出严重缺陷。Th-AC1KO小鼠在桶状结构模式方面表现出更严重的破坏。在这两个品系中，单丘脑皮质（TC）轴突标记显示，与对照组相比，第4层中TC轴突的横向范围更大。在第三个品系中，皮质兴奋性神经元中所有钙刺激型腺苷酸环化酶（AC1和AC8）均被删除。这些小鼠具有正常的桶状结构。综上所述，这些结果表明丘脑AC1在小鼠TC回路的模式形成和精细化中起主要作用。
