Dtnbp1 (dystrobrevin-binding protein 1 gene) 是一種與思覺失調症相關的遺傳因子。過去的文獻證實，剔除Dtnbp1 (Dys-/-) 會減弱小鼠記憶，包含工作記憶、恐懼記憶以及識別記憶，然而，很少有研究探討剔除Dtnbp1公鼠和母鼠對思覺失調症其一症狀-社交行為的影響。本篇研究結果顯示，Dys-/- 公鼠的社會階級較低於對照組wild-type (WT) 公鼠，反之，Dys-/- 母鼠的社交階級則較高於對照組WT母鼠。此外，Dys-/- 母鼠展現社交行為障礙，而Dys-/- 公鼠則無此行為缺陷。這些研究結果顯示Dtnbp1 gene會參與社交行為的表徵且存在性別上的差異。社交行為受大腦前額葉皮質區 (prefrontal cortex) 高度調控，因此針對Dys-/- 小鼠前額葉皮質進行分子及訊息傳遞路徑分析後，發現與對照組相比，Dys-/- 公鼠與母鼠的Activity-regulated cytoskeleton-associated protein (Arc) 蛋白皆顯著減少，Calcium/calmodulin-dependent protein kinase II (CaMKII) 活性在Dys-/- 公鼠也顯著減少，但在Dys-/- 母鼠中則沒有顯著差異。此外，在Dys-/- 公鼠前額葉皮質發現多巴胺Drd3受體mRNA表達顯著上升，然在Dys-/-母鼠前額葉皮質中則發現多巴胺Drd1以及Drd2受體mRNA表達水平下降，進一步分析Dys-/- 母鼠前額葉皮質多巴胺Drd2受體下游訊息傳遞路徑，發現GSK3β活性顯著降低。當Dys-/- 母鼠以管餵餵食多巴胺Drd2受體激動劑的抗精神病藥物銳思定膜衣錠 (brexpiprazole) 14天後，這些小鼠有改善社交行為之趨勢。綜合上述結果顯示Dtnbp1參與調控多巴胺神經途徑以及影響小鼠社交行為能力，也為治療思覺失調症提供新的見解。;The dystrobrevin-binding protein 1 gene (Dtnbp1) has been identified as one of genes associated with schizophrenia. Previous studies have demonstrated that working memory、fear and recognition memory were damaged in Dys-/- mice. However, there is no studies exploring whether mutation of Dtnbp1 in male and female mice exhibit deficits in social behavior since social dysfunction is one of pathologoical hallmarks seen in patients with schizophrenia. The current study showed that dominance hierarchy differed in both male and female Dys-/- mice compared with their wild-type (WT) littermate. Additionally, female Dys-/- mice were unable to recognize new partner versus old partner in three chamber social interaction test, while male Dys-/- exhibited preferred to interact with new partener in such test. These results indicated that Dtnbp1 gene is involved in sex-specific social behavior. At the cellular level, male and female Dys-/- shared common and distinct cellular signaling in the medial prefrontal cortex (mPFC), a brain region that is critical for social behavior. Specifically, both activity-regulated cytoskeleton-associated protein (Arc) protein expression and calcium/calmodulin-dependent protein kinase II (CaMKII) activity were downregulated in the mPFC of male Dys-/- mice compared wht WT littermate. However, Arc level, but not CaMKII activity, in the mPFC was decreased only in female Dys-/- mice compared to their WT littermate. At the molecular level, dopamine receptor D3 (Drd3) was the only type of dopamine receptors diminished in the mPFC of male Dys-/-mice. Interesting, dopamine receptor D1 and D2 (Drd1, Drd2) in the mPFC were both reduced in female Dys-/- mice compared with WT mice. The decrease in Drd2 expression in the mPFC was in corresponding to downregulation of GSK3β activity in female Dys-/- mice. Lastly, treatment with the antipsycotic brexpiprazole in female Dys-/- mice for 14 days showed a trend toward an increase in social interaction. Taken together, the results suggested that Dtnbp1 gene is involved in regulating dopamine signaling, which ultimately influences social behavior. This study provides a new insight into therapeutic approach in treating schizophrenia.
