Canales Cesar P, Lozano Stephanie, Frost Nicholas A, Cichewicz Karol, Amaral Wellington, Seban Nicolas, Fenton Ethan, Wade Ayanna, Chu Nickolas, Smith Emily, Ardekani Cory, Frank Samuel, Bennett Jeffrey, Lavenex Pierre, Kopley-Smith Aspen, Rahbarian Darlene, Corea Melissa, Perla Daniela, Davis Liam, Zhu Jiyuan, Ortiz Rebecca, Beauregard Paris, Moyer Caitlin, Baker Jacob, Sun Jingqi, Ma Boxuan, Lu Ju, Sohal Vikaas S, Amaral David, Zuo Yi, Nord Alex S
UC Davis Center for Neuroscience, Davis, CA 95618, USA.
Department of Psychiatry and Behavioral Sciences, University of California Davis, Sacramento, CA 95817, USA.
bioRxiv. 2025 Jun 4:2025.06.04.657776. doi: 10.1101/2025.06.04.657776.
mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nuclei transcriptomics (snRNA-seq), we found increased cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive and conditional mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.
突变会导致自闭症谱系障碍、认知缺陷和巨头畸形。小鼠模型表现出巨头畸形和转录病理学特征，在神经发生、神经元功能和行为方面的研究结果并不一致。通过体视学和单核转录组学（snRNA-seq），我们发现皮质体积增加并非由神经元数量增加所致。不同皮质细胞类型存在差异表达（DE），兴奋性神经元表现出较高的DE负担以及共享和亚类特异性的DE特征。组成型和条件型小鼠的批量RNA-seq DE鉴定出共享的转录病理学特征。突触体mRNA与核mRNA的DE鉴定出重叠的差异表达基因（DEG），但也存在显著差异和突触体变化的夸大现象。基于涉及谷氨酸能神经元的DE研究结果，我们发现小鼠表现出兴奋性神经元棘密度和动力学改变、GCaMP活性相关性降低以及睡眠紊乱。因此，单倍剂量不足会导致持续性兴奋性神经元功能障碍，扰乱转录以外的RNA调控，并影响神经元特性、皮质微电路和行为。
