利用大白鼠模式探討新生期投予 Dexamethasone 對海馬迴中麩胺酸突觸傳遞的影響

Abstract

Dexamethasone (DEX) 是一種人工合成的糖皮質激素,為常用的 消炎藥,也應用於早產兒的呼吸窘迫症之治療,它可有效地降低早產 兒,因為肺部發育不全,所引起的慢性呼吸性疾病 (chronic lung disease) 之發生機率。前人的研究發現,在大白鼠新生期時投予 DEX,可能會導致動物於青少年期產生記憶障礙,也會影響海馬迴 (hippocampus) 長期增益現象 (long-term potentiation ; LTP) 之形 成。相關研究也指出,新生期投予 DEX 會導致下視丘-腦下垂體-腎 上腺機制 (hypothalamic-pituitary-adrenal ; HPA axis) 反應失調,造成 動物於成年期時,產生不良的情緒反應和恐懼記憶。為釐清其可能的 不良影響,本實驗利用 Wistar 大白鼠,於幼鼠出生後第一到第三天, 以皮下注射的方式,給予遞減式劑量的 DEX。結果顯示,在新生期 給予 DEX 的幼鼠,與控制組相比較,其體重的增加會有明顯減緩的 趨勢,到六週齡時,仍呈現顯著的差異。 由於麩胺酸傳遞 (glutamatergic transmission) 是海馬迴中神經細 胞重要的傳遞方式,其作用和長期增益效應(LTP)的形成有著密切的 關聯,過程中需要細胞膜上的麩胺酸 AMPA 型受體及 NMDA 型受 體的參與,這兩種受體會和麩胺酸結合,再藉由一連串的訊息傳遞反 應,使得 LTP 得以形成。我們假設在新生期投予 DEX 可能藉由影響 到海馬迴上的麩胺酸受體的表現或功能,進而干擾了 LTP 的產生。 本研究利用離體的胞外電生理記錄、西方墨點法進行測試,以驗證此 項假設是否正確。 實驗結果顯示,在新生期接受 DEX 的處理,會影響青少年期大 6 白鼠海馬迴 LTP 的形成,而投予 NMDA 受體的促進劑,可使 LTP 回復正常。Synthetic glucocorticoid dexamethasone (DEX) is frequently used as a therapeutic agent to lessen the morbidity of chronic lung disease in premature infants. Pervious studies revealed that the neonatal DEX treatment would alter hippocampal synaptic plasticity in juvenile. Little is known about the long-term effect of neonatal DEX treatment on amygdale function. The current study is aimed to evaluate the long-term effect of neonatal DEX treatment on amygdale synaptic plasticity. To achieve this goal, male adult Wistar rats were subjected to receive subcutaneous injection (sc) of tapering doses of DEX (0.5 mg/kg, 0.3 mg/kg and 0.1mg/kg) from postnatal day 1 to 3, PN1~PN3. Animals were then subjected to electrophysiological recording at the age of 6 weeks. Our results showed that neonatal DEX treatment temporally decreased body weight of young rats, but did not affect that persistently to older age when compared with the control rats. In addition, neonatal DEX also treatment affected the formation of hippocampal long-term potentiation LTP. Neonatal DEX treated animals showed an apparent impairment on hippocampus LTP formation which can be partial restored by NMDA receptor agonist D-cycloserine. These results suggested that neonatal DEX treatment would exhibit a long-term adverse effect on hippocampal function. Further experiments will be required to elucidate the detail mechanism regarding to the long-term adverse effect of neonatal DEX treatment on hippocampal function.