Dysfunctional dendritic arborization is a key feature of many developmental neurological disorders. Across various human brain regions, basal dendritic complexity is known to increase along a caudal-to-rostral gradient. We recently discovered that basal dendritic complexity of layer II/III cortical pyramidal neurons in the mouse increases along a caudomedial-to-rostrolateral gradient spanning multiple regions, but at the time, no molecules were known to regulate that exquisite pattern. Integrin subunits have been implicated in dendritic development, and the subunit with the strongest associations with autism spectrum disorder and intellectual disability is integrin β3 (Itgb3). In mice, global knockout of Itgb3 leads to autistic-like neuroanatomy and behavior. Here, we tested the hypothesis that Itgb3 is required for increasing dendritic complexity along the recently discovered tangential gradient among layer II/III cortical pyramidal neurons. We targeted a subset of layer II/III cortical pyramidal neurons for Itgb3 loss-of-function via Cre-loxP-mediated excision of Itgb3. We tracked the rostrocaudal and mediolateral position of the targeted neurons and reconstructed their dendritic arbors. In contrast to controls, the basal dendritic complexity of Itgb3 mutant neurons was not related to their cortical position. Basal dendritic complexity of mutant and control neurons differed because of overall changes in branch number across multiple branch orders (primary, secondary, etc.), rather than any changes in the average length at those branch orders. Furthermore, dendritic spine density was related to cortical position in control but not mutant neurons. Thus, the autism susceptibility gene Itgb3 is required for establishing a tangential pattern of basal dendritic complexity among layer II/III cortical pyramidal neurons, suggesting an early role for this molecule in the developing brain.

中文翻译：

---

整合素β3沿切向梯度组织大脑皮层锥体神经元的树突复杂性

功能失调的树突状树枝化是许多发育性神经系统疾病的一个关键特征。在人类大脑的各个区域中，已知基底树突的复杂性沿着尾部到嘴的梯度增加。我们最近发现，小鼠中 II/III 层皮质锥体神经元的基底树突复杂性沿着跨多个区域的尾内侧到头外侧梯度增加，但当时，没有任何分子可以调节这种精致的模式。整合素亚基与树突发育有关，与自闭症谱系障碍和智力障碍相关性最强的亚基是整合素 β3 (Itgb3)。在小鼠中，Itgb3 的整体敲除会导致类似自闭症的神经解剖学和行为。这里，我们测试了一个假设，即沿着最近发现的 II/III 层皮质锥体神经元之间的切向梯度增加树突复杂性需要 Itgb3。我们通过 Cre-loxP 介导的 Itgb3 切除，针对 Itgb3 功能丧失的 II/III 层皮质锥体神经元的一个子集。我们跟踪了目标神经元的 rostrocaudal 和中间外侧位置，并重建了它们的树突乔木。与对照相比，Itgb3 突变神经元的基底树突复杂性与其皮质位置无关。突变和控制神经元的基础树突复杂性不同，因为跨多个分支顺序（初级、二级等）的分支数量的整体变化，而不是这些分支顺序的平均长度的任何变化。此外，树突棘密度与对照中的皮质位置有关，但与突变神经元无关。因此，自闭症易感基因 Itgb3 是在 II/III 层皮质锥体神经元之间建立基底树突复杂性的切向模式所必需的，这表明该分子在发育中的大脑中具有早期作用。