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Disrupted in Schizophrenia 1 Reverse Ectopic Migration of Neural Precursors in Mouse Hilus After Pilocarpine-Induced Status Epilepticus

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Abstract

Neural precursors in the subgranular zone (SGZ) can be stimulated by status epilepticus (SE) and ectopically migrate to the hilus. These mislocated cells serve as “potential pacemakers” of spontaneous recurrent seizures, and targeting them could potentially reverse the seizure process. Disrupted-in-Schizophrenia 1 (DISC1) regulates hippocampal neurogenesis after seizures both in vitro and in vivo. Our previous study found that DISC1 was colocalized with neural precursors in the hilus after SE. However, its molecular mechanism and pathways contribute to the ectopic migration of neural precursors to the hilus induced by SE awaits exploration. Here, we showed that both Reelin-ApoER2/EphB2 and Reelin-Integrin β1/Integrin α5 axes may participate in the modulation of neurogenesis after SE. Especially, DISC1, as a protective role, might partly reversed the ectopic progenitor migration via EphB2 pathway. Our findings demonstrated that DISC1 played a protective role in the ectopic migration of neural precursors induced by SE insults and DISC1 could be an attractive new target for the treatment of epilepsy.

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All data generated or analyzed in this study are available in the published article.

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Funding

This work was supported by the National Natural Science Foundation of China (82160260, 81601134 to Q.W, 82160261 to Y. H. ), the Yunnan Health Training Project of High-Level Talents (H-2018056 to Q.W., L-2019019 to Y. H.), the Young and Middle-aged Academic and Technical Leaders Reserve Talents Project of Yunnan Province Science and Technology Department (202205AC160019 to Q.W.), Yunnan Applied Basic Research Projects (202201AY070001-083 to Q.W.), and the Scientific Research Fund Project of the Education Department of Yunnan Province (2022Y218 to L.C.).

Author information

Author notes

  1. Lu Chen

    Present address: Department of Neurology, First Affiliated Hospital, Kunming Medical University, 295 Xi Chang Road, Kunming, Yunnan, 650032, People’s Republic of China

  2. Yanbing Han and Qian Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, First Affiliated Hospital, Kunming Medical University, 295 Xi Chang Road, Kunming, Yunnan, 650032, People’s Republic of China

    Jing Xu, Lin Zhu, Lvhua Chang, Yanbing Han & Qian Wu

  2. Department of Neurology, Northeast Yunnan Hospital, Mengquan Avenue, Zhaoyang District, Zhaotong, Yunnan, 657000, People’s Republic of China

    Puying Xu

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  1. Lu Chen
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Contributions

Qian Wu: conceived and designed experiments. Lu Chen, Jing Xu, Lin Zhu, and Puying Xu: performed experiments and analyzed the data. Lu Chen, Jing Xu, and Lin Zhu: wrote the paper and final approval of the manuscript. Lu Chen, Puying Xu, and Lvhua Chang: prepared the figures. Qian Wu, Yanbing Han and Lu Chen: responded funding. Qian Wu, Yanbing Han, and Lvhua Chang: critically reviewed and commented on the manuscript.

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Correspondence to Yanbing Han or Qian Wu.

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All animal-based experiments were according to the requirements of the Chinese Animal Ethics Committee and approved by Kunming Medical University.

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Highlights

1) DISC1 might partly reverse the ectopic migration of neural precursors to the hilus via EphB2 pathway after SE;

2) Both Reelin-ApoER2/EphB2 and Reelin-Integrin β1/Integrin α5 axes may participate in the modulation of neurogenesis after SE;

3) DISC1 may play a protective role in the neurogenesis response to SE.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Fig. 1

Expression of DISC1 and DCX in the hilus. After SE, DCX + cells increased in the SGZ and migrated ectopically to the hilus. No co-localization of DISC1 and DCX was observed. Green fluorescence labels DISC1, red fluorescence labels DCX, and blue fluorescence labels the nucleus. The white arrows show ectopically migrated DCX + cells, scale bar = 20 μm. (PNG 5.73 MB)

High Resolution Image (TIF 26.1 MB)

Supplementary Fig. 2

Co-expression of DISC1 and Reelin in the hilus. DISC1 co-localized with Reelin in the SGZ and the hilus. The white arrows show DISC1+/ Reelin + cells, red fluorescence labels DISC1, green fluorescence labels Reelin, and blue fluorescence labels the nucleus, scale bar = 20 μm. (PNG 3.42 MB)

High Resolution Image (TIF 22.7 MB)

Supplementary Fig. 3

Co-expression of DISC1 and EphB2 in the hilus. DISC1 co-localized with EphB2 in the SGZ and the hilus. The white arrows show DISC1+/ EphB2 + cells, red fluorescence labels DISC1, green fluorescence labels EphB2, and blue fluorescence labels the nucleus, scale bar = 20 μm. (PNG 3.98 MB)

High Resolution Image (TIF 22.8 MB)

Supplementary Fig. 4

Co-expression of DISC1 and Integrin β1 in the hilus. DISC1 co-localized with Integrin β1 in the GCL, SGZ, and the hilus. The white arrows show DISC1+/ Integrin β1 + cells, red fluorescence labels DISC1, green fluorescence labels Integrin β1, and blue fluorescence labels the nucleus, scale bar = 20 μm. (PNG 6.02 MB)

High Resolution Image (TIF 26.0 MB)

Supplementary Fig. 5

Co-expression of DISC1 and Integrin α5 in the hilus. DISC1 co-localized with Integrin α5 in the GCL, SGZ, and the hilus. The white arrows show DISC1+/ Integrin α5 + cells, red fluorescence labels DISC1, green fluorescence labels Integrin α5, and blue fluorescence labels the nucleus, scale bar = 20 μm. (PNG 5.73 MB)

High Resolution Image (TIF 26.2 MB)

Supplementary Fig. 6

Co-expression of DISC1 and Reelin in the hilus after DISC1 up-regulation. DISC1 co-localized with Reelin in the GCL, SGZ, and the hilus. The white arrows show DISC1+/ Reelin + cells, red fluorescence labels DISC1, green fluorescence labels Reelin, and blue fluorescence labels the nucleus, scale bar = 20 μm. (PNG 1.94 MB)

High Resolution Image (TIF 12.0 MB)

Supplementary Fig. 7

Co-expression of DISC1 and EphB2 in the hilus after DISC1 up-regulation. DISC1 co-localized with EphB2 in the GCL, SGZ, and the hilus. The white arrows show DISC1+/ EphB2 + cells, red fluorescence labels DISC1, green fluorescence labels EphB2, and blue fluorescence labels the nucleus, scale bar = 20 μm. (PNG 2.29 MB)

High Resolution Image (TIF 12.1 MB)

Supplementary Fig. 8

Co-expression of DISC1 and Integrin β1 in the hilus after DISC1 up-regulation. DISC1 co-localized with Integrin β1 in the GCL, SGZ, and the hilus. The white arrows show DISC1+/ Integrin β1 + cells, red fluorescence labels DISC1, green fluorescence labels Integrin β1, and blue fluorescence labels the nucleus, scale bar = 20 μm. (PNG 2.49 MB)

High Resolution Image (TIF 12.3 MB)

Supplementary Fig. 9

Co-expression of DISC1 and Integrin α5 in the hilus after DISC1 up-regulation. DISC1 co-localized with Integrin α5 in the GCL, SGZ, and the hilus. The white arrows show DISC1+/ Integrin α5 + cells, red fluorescence labels DISC1, green fluorescence labels Integrin α5, and blue fluorescence labels the nucleus, scale bar = 20 μm. (PNG 2.15 MB)

High Resolution Image (TIF 12.1 MB)

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Chen, L., Xu, J., Zhu, L. et al. Disrupted in Schizophrenia 1 Reverse Ectopic Migration of Neural Precursors in Mouse Hilus After Pilocarpine-Induced Status Epilepticus. Mol Neurobiol 60, 6689–6703 (2023). https://doi.org/10.1007/s12035-023-03507-4

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