Effects of Lipopolysaccharide on the Brain NMDA Receptor and GABAA Receptor Expression in the Valproic Acid-induced Autism-like Animal Model

• Main Authors: Chung-Han Weng, 翁崇瀚
• Other Authors: Yi-Hsuan Lee
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/49216232239530458920

碩士 === 國立陽明大學 === 生理學研究所 === 101 === Autism spectrum disorder (ASD) is a group of neurodevelopmental disability that can result in significant social, behavioral and communication challenges. Accumulating evidences have demonstrated that disruption of excitatory-inhibitory (E/I) balance in the central nervous system (CNS) may be one of the most crucial causes of autistic phenotypes. Previous reports indicated that maternal or early life neuroinflammation is related to an increased risk of ASD in children. Several reports have depicted elevation of inflammatory factors from ASD subjects in basal level as well as after lipopolysaccharide (LPS) stimulation in the CNS and peripheral blood, implying the endogenous chronic inflammatory effect may contribute to the pathogenesis of ASD. However, it remains unknown whether the exogenous inflammatory insult affects autism-like behavior by altering excitatory or inhibitory transmission in the animal model of autism. In the present study, we hypothesized that LPS, a well known bacterial endotoxin used for inducing inflammatory responses, would affect the behavioral pattern and the expression of glutamate receptors and GABAA receptors in autistic brains. Maternal valproic acid (VPA) administration-induced ASD-like offspring has been showed with E/I imbalance in the synaptic transmission, and was used as the animal model of autism in this study. Our results demonstrated that VPA-exposed offspring rats revealed social impairment, higher N-methyl-D-aspartate (NMDA) receptor subunits expression and lower GABAAR β3 level in the medial prefrontal cortex (mPFC) as compared with the control group. Suprisingly, bilateral intracerebroventricular (ICV) injection of LPS at a dosage of 10-200 μg after 24hr significantly corrected the impairment of social interaction in prenatally VPA-exposed rats, whereas the high dose LPS (400 ug) treatment had no such effect. Western blot analysis shows that 10 μg LPS not only induces expression of inflammatory factors, but also has tendency to reverse protein level of NMDA receptor NR2B subunit in mPFC of VPA-exposed offspring. In contrast, GABAA receptor β3 subunit expression is not altered by the LPS treatment in the mPFC of VPA-exposed offspring. In conclusion, our results suggest that low dosage of LPS may modify the impaired synaptic E/I balance in autistic CNS and further correct social behavioral deficit in VPA-induced ASD-like animal model by adjusting the expression of excitatory NMDA receptor without affecting inhibitory GABAA receptor expression.