| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 89 === We have previously found that integrin-associated protein (IAP) gene expression is significantly related to memory formation in rats by using the polymerase chan reaction (PCR) differential display method. The quantitative reverse transcription-PCR analysis also revealed that IAP expression was induced 4-fold higher at 3-hr after training in the hippocampus of rats showing good retention performance. Antisense oligonucleotides to IAP also markedly impaired retention performance and inhibited long-term potentiation (LTP) in rats. IAP is a 50-kD ubiquitously expressed membrane glycoprotein that is associated with integrin and belongs to the immunoglobulin superfamily of receptors. IAP is known to widely exist in hematopoietic cells and plays a critical role in cell signaling of the immune system, but little research investigates its role in neurons. IAP acts as a receptor for the cell binding domain (CBD) of thrombospondin (TSP) matrix protein family, which induces neurite outgrowth. The specific aim of the present study is to investigate how IAP might act to facilitate memory formation. In the first part, we have used the gene-targeted integrin-associated protein-deficient mice (IAP-/-) to further investigate the role of IAP involved in memory formation and LTP in vivo. We adopted the one-way inhibitory avoidance learning task as the behavioral paradigm. Results revealed that there was a significant impairment in memory retention and a significant redutction in the magnitude of LTP in IAP-deficient mice when compared with the homozygote (IAP+/+) and heterozygote (IAP+/-) mice. The results indicate that IAP plays an important role in the process of memory formation and synaptic plasticity in mice as well as in rats. In the second part, we found that a function-blocking anti-IAP mAb, miap301, inhibited hippocampal LTP in vivo and impaired memory formation in mice. Meanwhile, IAP mAb was shown to block the adhesion of granular neurons to TSP-coated substrates. It implicates that IAP might act through binding to the candidate ECM protein, TSP, and subsequently activated the signal transduction pathway associated with memory formation. At a dose that affectively impairing both memory retention and LTP, IAP mAb also significantly blocked potassium chloride-induced glutamate release from the hippocampus in vivo. Results from western blot confirmed the presence of IAP at the synaptic area. These results suggest that IAP mAb may impair synaptic plasticity and behavioral plasticity in mice through blockade of granular cell attachment to ECM protein and the subsequent signal transduction, and through inhibition of glutamate release from the hippocampus.
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