S-Space College of Natural Sciences (자연과학대학) Program in Brain Science (협동과정-뇌과학전공) Theses (Master's Degree_협동과정-뇌과학전공)
A Study on the Behavioral and Molecular Changes in the Cerebral Cortex and Hippocampus of a Valproic Acid-Induced Autism Mouse Model
발프로산에 의한 자폐증 동물 모델의 행동학적 이상 및 대뇌 피질과 해마에서의 분자적 변화에 관한 연구
- 우스만 마흐무드
- 자연과학대학 협동과정뇌과학전공
- Issue Date
- 서울대학교 대학원
- 학위논문 (석사)-- 서울대학교 대학원 : 협동과정뇌과학전공, 2015. 2. 김혜선.
- Introduction: Autism spectrum disorder (ASD) is a developmental disorder with manifestations of obscure neural development patterns, deficient dendritic arborization, molecular discrepancies and behavior impairments. Currently, 523 genes are linked with ASD and only 5% of all autistic patients have a genetic component. The remaining portion of ASD is thought to be associated with environmental factors. Given the vast amount of genetic discrepancy, there are currently over 540 different genetic autism mouse models and 20 environmentally induced models. Currently the valproic acid (VPA)-induced animal model is yet to be considered a valid autism animal model. VPA, an antiepileptic drug, is known to induce ASD if administered during pregnancy. The goal of this study is to elucidate behavioral and molecular changes that occur in an environmental mouse model as well as finding potential molecular targets that may explain autistic phenotypes.
Methods: In order to investigate molecular pathways in VPA-induced autism mice, western blotting, immunohistochemistry, Golgi-Cox staining, Nissl staining, dendritic spine analysis were used. In addition, to examine behavioral alterations in the mouse model, self-righting, eye opening, mother scent choice, thermal nociception, self-grooming, home cage interaction, three chamber social interaction, T-maze, open field and elevated plus-maze tests were performed.
Results: VPA mice showed impairments in developmental milestones, social interaction, repetitive behavior and spatial memory. VPA mice also exhibited difference in dendritic spine density and had an increase in the amount of mushroom and thin spine types shown in the cerebral cortex. VPA mice also showed deregulation of molecular pathways, i.e.
PTEN and P-AKT in the cerebral cortex and hippocampus throughout development and post-weaning period.
Conclusion: VPA mice show severe impairments in development, and mimic several different autistic molecular patterns reported previously. I showed that VPA mice show consistent synaptic abnormalities in early as well as post-weaning period coinciding with deregulations of PTEN expression in the hippocampus and cortex. Taken together, this study suggests that PTEN may be an important causative gene which has implications in synaptic disruption and behavioral changes observed in ASD with an environmental etiology.