自閉症相關基因-Dlgap2 突變鼠表現異常嗅覺性徵

Abstract

嗅覺是腦中一個相當古老的系統，其在哺乳類中有建立社會行為的作用。然 而，至今嗅覺與社會行為的分子機制仍不清楚。臨床研究發現，一個突觸後蛋白 -DLGAP2 與泛自閉症(autism spectrum disorder, ASD)病人的社會表現損害有關。目前已知Dlgap2 在囓齒類的嗅覺系統有高度表現，故Dlgap2 在嗅覺及社會行為的角色需被闡明。 利用Cre/lox 系統，Dlgap2 基因的第六外顯子被剔除，Dlgap2 剔除(knockout,KO)鼠而後製造出來。嗅覺系統的結構及功能則利用生物化學、型態及行為觀察檢定。 雖然Dlgap2 剔除鼠的嗅覺偵測及嗅覺區分能力和野生型 (wildtype, WT)無異，但是Dlgap2 剔除鼠卻對社會味道表現高度反應。此外與野生型鼠比較，一個AMPA 受器-GluR1 在Dlgap2 剔除鼠的嗅球表現量增加。型態方面，Dlgap2剔除鼠在梨狀皮質(piriform cortex)中的表層錐狀細胞(superficial pyramidal cell)的樹突(dendrite)總長度和節點數上升，而樹突突起(dendritic spine)密度卻下降。 嗅球的突觸蛋白改變及嗅覺皮質的樹突結構改變可能造成Dlgap2 剔除鼠對於社會訊息的偵測或解釋異常，並可說明社會味道所引發的高反應性。

The olfactory system, a relatively primitive system in the brain, plays an important role in the establishment of social behaviors in mammals. However, the molecular mechanisms regarding olfaction and social behavior are still largely unclear.Clinical research has suggested an association between DLGAP2, encoding a postsynaptic protein, and impaired social performance in patients of autism spectrum disorder (ASD). It is clear that Dlgap2 is highly expressed in the olfactory system in rodents, the roles of Dlgap2 in olfaction and social behavior can thus be elucidated. Using the cre/lox system, exon 6 of Dlgap2 gene was deleted and Dlgap2 knockout (KO) mice were subsequently generated. The structure and function of the olfactory system were examined with biochemical, morphological and behavioral means. In Dlgap2 KO mice, olfactory detection and discrimination were comparable to those in wildtype (WT) littermates. However, they demonstrated hyperactivity towards social odors. Compared with WT mice, the expression of GulR1, a key component of AMPA receptor, was increased in the olfactory bulb of Dlgap2 KO mice. In the morphological aspect, the dendritic length was longer and number of segments was increased in superficial pyramidal cells of the piriform cortex in Dlgap2 KO mice while the spine density was reduced. Changes of synaptic proteins in the olfactory bulb and altered dendritic structures in the olfactory cortex might contribute to the disturbance of detection or interpretation of social signals which might account for social odor-induced hyperactivity in Dlgap2 KO mice.