A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development
Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 (DISC1), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Oncotarget - 8(2017), 49 vom: 17. Okt., Seite 84798-84817 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Deng, Dazhi [VerfasserIn] |
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| Links: |
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| Themen: |
DISC1 |
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| Anmerkungen: |
Date Revised 20.11.2019 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.18632/oncotarget.21381 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 (DISC1), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Pathology Section | |
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| 700 | 1 | |a Jian, Chongdong |e verfasserin |4 aut | |
| 700 | 1 | |a Lei, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yijing |e verfasserin |4 aut | |
| 700 | 1 | |a McSweeney, Colleen |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Fengping |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Yilun |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Donghua |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yonggang |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Limin |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Yingwei |e verfasserin |4 aut | |
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