Department of Life Sciences, University of Trieste, Trieste, 34127, Italy.
IRCCS Ospedale Policlinico San Martino, Genoa, 16132, Italy.
Mol Brain. 2023 Jun 9;16(1):49. doi: 10.1186/s13041-023-01031-z.
The relationship between autism spectrum disorder (ASD) and dendritic spine abnormalities is well known, but it is unclear whether the deficits relate to specific neuron types and brain regions most relevant to ASD. Recent genetic studies have identified a convergence of ASD risk genes in deep layer pyramidal neurons of the prefrontal cortex. Here, we use retrograde recombinant adeno-associated viruses to label specifically two major layer V pyramidal neuron types of the medial prefrontal cortex: the commissural neurons, which put the two cerebral hemispheres in direct communication, and the corticopontine neurons, which transmit information outside the cortex. We compare the basal dendritic spines on commissural and corticopontine neurons in WT and KO mice for the ASD risk gene Itgb3, which encodes for the cell adhesion molecule β3 integrin selectively enriched in layer V pyramidal neurons. Regardless of the genotype, corticopontine neurons had a higher ratio of stubby to mushroom spines than commissural neurons. β3 integrin affected selectively spine length in corticopontine neurons. Ablation of β3 integrin resulted in corticopontine neurons lacking long (> 2 μm) thin dendritic spines. These findings suggest that a deficiency in β3 integrin expression compromises specifically immature spines on corticopontine neurons, thereby reducing the cortical territory they can sample. Because corticopontine neurons receive extensive local and long-range excitatory inputs before relaying information outside the cortex, specific alterations in dendritic spines of corticopontine neurons may compromise the computational output of the full cortex, thereby contributing to ASD pathophysiology.
自闭症谱系障碍 (ASD) 与树突棘异常之间的关系众所周知，但目前尚不清楚这些缺陷是否与与 ASD 最相关的特定神经元类型和大脑区域有关。最近的遗传研究表明，ASD 风险基因在额前皮质的深层锥体神经元中存在汇聚。在这里，我们使用逆行重组腺相关病毒特异性标记额前皮质内侧面的两个主要的 V 层锥体神经元类型：联络神经元，它使两个大脑半球直接通讯；皮质桥核神经元，它将信息传递到皮质之外。我们比较了 WT 和 KO 小鼠中 ASD 风险基因 Itgb3 上的共位和皮质桥核神经元的基底树突棘，Itgb3 编码细胞黏附分子β3 整合素，选择性富集在 V 层锥体神经元中。无论基因型如何，皮质桥核神经元的短粗棘突与蘑菇棘突的比例都高于联络神经元。β3 整合素选择性影响皮质桥核神经元的棘突长度。β3 整合素的缺失导致皮质桥核神经元缺乏长 (>2μm) 细树突棘。这些发现表明，β3 整合素表达的缺乏特异性地损害了皮质桥核神经元的不成熟棘突，从而减少了它们可以采样的皮质区域。因为皮质桥核神经元在将信息传递到皮质之外之前会接收到广泛的局部和长程兴奋性输入，所以皮质桥核神经元的树突棘的特定改变可能会损害整个皮质的计算输出，从而导致 ASD 的病理生理学。
