Oncotarget

Research Papers: Pathology:

A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development

Dazhi Deng, Chongdong Jian, Ling Lei, Yijing Zhou, Colleen McSweeney, Fengping Dong, Yilun Shen, Donghua Zou, Yonggang Wang, Yuan Wu, Limin Zhang _ and Yingwei Mao

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Oncotarget. 2017; 8:84798-84817. https://doi.org/10.18632/oncotarget.21381

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Abstract

Dazhi Deng1,2, Chongdong Jian2,3, Ling Lei2,4, Yijing Zhou2, Colleen McSweeney2, Fengping Dong2, Yilun Shen2, Donghua Zou5, Yonggang Wang6, Yuan Wu3, Limin Zhang7 and Yingwei Mao2

1 Department of Emergency, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China

2 Department of Biology, Pennsylvania State University, University Park, PA, USA

3 Department of Neurology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China

4 Health Examination Center, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China

5 Department of Neurology, The First People’s Hospital of Nanning, Nanning, Guangxi, China

6 Department of Neurology, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, China

7 CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China

Correspondence to:

Limin Zhang, email:

Yingwei Mao, email:

Keywords: DISC1, interneuron, neural progenitors, metabolism, depression, Pathology Section

Received: March 14, 2017 Accepted: September 03, 2017 Published: September 28, 2017

Abstract

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 andspatialregulation. 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.


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