Molecular Mechanisms Of Neuropsychiatric Diseases

Author : Fengping Dong
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (111 download)

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Download or read book Molecular Mechanisms of Psychiatric Risk Genes Underlying Neurodevelopment and Behaviors written by Fengping Dong and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Psychiatric diseases are to a group of mental illnesses that alter the cognition, emotion, and behavior of patients. The most common psychiatric diseases include autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder, anxiety disorder, bipolar disorder, depression, obsessive-compulsive disorders, and schizophrenia spectrum disorders (SSDs). ASDs and SSDs show strong pattern of inheritance, implicating a likely genetic origin for these diseases. Inherited mental disorders frequently show symptoms at the childhood or adolescent stage, indicating that risk genes are critical for neurodevelopment. ASD and SSD risk genes have been explored using linkage studies, genome-wide association studies (GWAS), and copy number variation (CNV) analysis. Animal disease models are powerful tools to understand the mechanism of disease-inducing psychiatric risk genes because neurodevelopment and behavioral changes associated with the disease can be monitored. Here, we utilize genome editing techniques and the cre-lox recombination system to investigate how risk genes contribute to psychiatric diseases. Schizophrenia is the major diagnostic disease in the SSDs. The first gene to reach genome-wide significance in GWAS for schizophrenia is ZNF804A, which encodes a zinc-finger protein. The single nucleotide polymorphism (SNP) rs1344706 has a risk allele (A) localized in an intron of ZNF804A. Schizophrenia patients with the risk allele (A) of rs1344706 show altered expression of ZNF804A. In addition, CNV analyses have implicated ZNF804A in patients with ASDs, anxiety disorder, and bipolar disorder. However, its molecular functions in the brain are not clear. To understand how ZNF804A regulate neurite development, we overexpressed the gene in primary cultured neuronal progenitor cells. We found that ZNF804A overexpression attenuated neurite outgrowth. These deficits can be reversed by overexpression of FEZ1, which was identified through a yeast two-hybrid (Y2H) screen as a protein that interacted with ZNF804A. However, galectin-1, the other binding partner of ZNF804A, cannot restore the neurite outgrowth deficits. To further explore the role of ZNF804A in schizophrenia, we generated Zfp804a deletion in mice using CRISPR/Cas9 genome editing technique. The Zfp804a deletion mice exhibited a reduced prepulse inhibition, which was used to assess the positive symptoms in schizophrenia mouse models. The Zfp804a deletion mice also showed female-specific hyperlocomotion in the open field test and the elevated plus maze test. We also confirmed the increased hyperactivity of Zfp804a deletion mice using IntelliCage. To elucidate the molecular function of ZNF804A, we utilized the crosslinking immunoprecipitation (CLIP) method to isolate and identify the transcriptomic binding targets of ZNF804A. This analysis revealed a specific RNA sequence with high affinity to the RNA-binding protein ZNF804A. Functional enrichment analysis indicated that the RNA targets of ZNF804A are enriched in RNA processing, RNA transport, translation, and mitochondrial function. In addition to the SNPs identified by GWAS, psychiatric risk genes have also been reported in patients with rare mutations. For example, mutations in -catenin (CTNNB1) have been linked to intellectual disabilities, and rare mutations were identified in patients with ASD. As a key regulator of the canonical Wnt pathway, CTNNB1 has an essential role in neurodevelopment. However, the function of CTNNB1 in specific neuronal subtypes is unclear. To understand how CTNNB1 deficiency contributes to ASDs, we generated CTNNB1 conditional knockout mice (cKO) in parvalbumin (PV) interneurons. CTNNB1 cKO mice have increased anxiety, but have no overall change in motor function. Interestingly, mice harboring a CTNNB1 cKO in PV interneurons exhibited significantly impaired object recognition and social interactions as well as elevated repetitive behaviors, which mimic the core symptoms of patients with ASD. Surprisingly, deletion of CTNNB1 in PV interneurons enhanced spatial memory. Regarding the effects of CTNNB1 deficiency on overall neuronal activity, we found that c-fos was significantly reduced in the cortex, but not in the dentate gyrus and the amygdala. Our findings revealed that CTNNB1 regulated cognitive and autistic-like behaviors. Our studies have important implications for understanding how risk genes contribute to psychiatric diseases. These findings reveal potential therapeutic targets for patients with schizophrenia carrying the ZNF804A risk allele or for ASD patients harboring the CTNNB1 mutation.