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Dentate Gyrus Morphogenesis is Regulated by an Autism Risk Gene Trio Function in Granule Cells

 Mengwen Sun1,2 · Weizhen Xue3  · Hu Meng1  · Xiaoxuan Sun1  · Tianlan Lu1  · Weihua Yue1,4  · Lifang Wang1  · Dai Zhang1,5,6  · Jun Li1,6
1 Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Key laboratory of Mental Health, Chinese Academy of Medical Sciences, Beijing 100083, China 
2 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China 
3 BGI-Beijing, Beijing 102601, China 
4 PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China 
5 Institute for Brain Research and Rehabilitation (IBRR), Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou 510631, China 
6 Changping Laboratory, Beijing 102299, China

Abstract
Autism Spectrum Disorders (ASDs) are reported as a group of neurodevelopmental disorders. The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes, but the underlying mechanisms are not fully understood. Here, we report that deletion of Trio, a high-susceptibility gene of ASDs, causes a postnatal dentate gyrus (DG) hypoplasia with a zigzagged suprapyramidal blade, and the Trio-deficient mice display autism-like behaviors. The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells (GCs), which further results in a migration deficit of neural progenitors. Furthermore, we reveal that Trio plays different roles in various excitatory neural cells by spatial transcriptomic sequencing, especially the role of regulating the migration of postmitotic GCs. In summary, our findings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.

Keywords
Trio; Autism spectrum disorders; Dentate gyrus morphogenesis; Neuron migration; Spatial transcriptomic sequencing