| Summary: | 碩士 === 國立陽明大學 === 生理學研究所 === 103 === Autism spectrum disorder (ASD) is general terms for a group of complex disorders of brain development that are characterized by significant social behavioral and communication challenges. Excitatory-inhibitory (E/I) and serotonin system imbalance in the central nervous system (CNS) may be the crucial causes of autistic phenotypes. The dorsal raphe nuclei (DRN), the medial prefrontal cortex (mPFC) and the amygdala are critically involved in neural circuitry of serotonin system. In previous study, the impairment of social behavior and excitatory/ inhibitory (E/I) imbalance in the lateral amygdala (LA) can be rescued by 8-OH-DPAT, a selective 5-HT1A receptor agonist, in VPA–induced rat animal model. However, the role of 5-HT1A receptor within the mPFC in autistic rats is unclear. Thus, we hypothesized that 8-OH-DPAT could ameliorate the impairment of behavior, rescue the E/I imbalance within the mPFC. Maternal valproic acid (VPA) administration-induced ASD-like offspring showed social impairment, anxiety-like behavior, hyperactivity, depression of paired-pulse facilitation (PPF), lower N-methyl-D-aspartate (NMDA) receptor subunits expression and higher gamma-Aminobutyric acid A receptor (GABAA receptor) β3 level in the mPFC as compared with the saline-exposed group. Surprisingly, local infusion of 8-OH-DPAT after 1 hr significantly corrected the impaired social behavior, anxiety-like behavior in rats and the mPFC incubated with 8-OH-DPAT rescued the decrease of paired-pulse ratio (PPR) in prenatally VPA exposure. In addition, 8-OH-DPAT local infusion had tendency to reverse protein level of NMDA receptor NR2B subunit and GABAA receptor β3 subunit expression in the mPFC of VPA-exposed offspring. Besides, we further investigated phosphorylated CaMKII expression in VPA-exposed rats which could elevate NR2B subunit within the mPFC while 5-HT1A receptor activation. The data showed that the decrease of phosphorylation of CaMKII expression was reversed by 8-OH-DPAT as the change of NR2B expression and these data implicated that NR2B elevated by 5-HT1A receptor activation through CaMKII phosphorylation. In conclusion, our results suggest that 8-OH-DPAT may modify the impaired synaptic E/I balance in autistic CNS and further correct social behavioral deficit, anxiety-like behavior in VPA-induced ASD-like animal model by adjusting the expression of excitatory NMDA receptor and inhibitory GABAA receptor expression.
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