| Summary: | 碩士 === 國立陽明大學 === 生理學研究所 === 106 === Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders that are characterized by social communication deficits, repetitive behaviors, and the impairment of cognitive functions. The hippocampus, an area of the brain that plays a critical role in cognitive function, has been reported to be abnormally developed in people with ASD. Central thalamic deep brain stimulation (CT-DBS) is a neurosurgical procedure that demonstrably improve several neurological diseases and regulate hippocampal activity, which is strongly correlated with cognitive function. However, the relationship between ASD and CT-DBS remains poorly described. Therefore, in this study, we investigated the effect of CT-DBS on autism-like phenotypes in valproic acid (VPA)-exposed offspring. To determine whether a synaptic mechanism is involved in CT-DBS, we tested CT-DBS in different current strength (0.2, 0.4, and 1.5 mA at 100-Hz biphasic stimulus, 25 μs per phase pulse, 30 min per day for 3 days) to analyze at which strength the long-term potentiation (LTP) of the hippocampus was enhanced. The results showed that a current strength above 0.4 mA can significantly enhance LTP in the hippocampus. Additionally, the impaired social behavior and repetitive behavior of VPA-exposed offspring were improved after 3 days of 0.4mA CT-DBS treatment. We also found the abnormal learning and memory in VPA-exposed offspring were improved after CT-DBS, which is measured by contextual fear conditioning. Furthermore, we found the VPA-exposed offspring had enhanced LTP in hippocampus, which can be reversed after CT-DBS treatment. We found the NMDA receptor subunit, NR2B, was increased in VPA exposed rat and it can also be reversed by CT-DBS. Furthermore, we discovered the activation of 5-HT1A receptor was involved in the mechanism of CT-DBS rescued the impaired behavior of VPA-exposed offspring by adding a single low dose of 5-HT1A receptor agonist, 8-OH-DPAT, with 1 days CT-DBS, which could also rescue the impaired behaviors, the increased NR2B and the enhanced LTP in hippocampus of VPA-exposed offspring. At last, we observed the 11, 12-EET, a lipid signaling molecule which can reduce the excitatory of hippocampal neuron, and the synthesis enzyme of 11, 12EET, which is CYP2J3, was increased by CT-DBS in VPA-exposed offspring. Overall, the CT-DBS alter the synaptic plasticity of hippocampus that may offer effective treatment in the VPA-induced ASD model.
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