Synapse-associated protein 90/PSD-95-associated protein 3 (SAPAP3) 是一個高度表現在紋狀體興奮性突觸的突觸後骨架蛋白。在過去的研究中報導過SAPAP3基因剔除小鼠會出現類強迫性行為及皮質投射到紋狀體的突觸傳遞缺陷。而有趣的是，在最近的文獻中指出，新生大鼠暴露到三環抗憂鬱藥clomipramine可能會在成熟大鼠產生類強迫症行為及症狀。然而，這個新的強迫症研究動物模式其在神經生物學上的依據仍未清楚。因此此研究的主要目的是去探討SAPAP3在新生大鼠投予clomipramine所誘導之類強迫症行為發生中所扮演的角色。實驗結果中，我們發現在大鼠出生第九天到第十六天每天投予兩次clomipramine，在大鼠成年早期進行自發性理毛實驗、埋藏彈珠實驗、明暗箱轉換實驗及架高十字迷宮，可以觀察到新生暴露clomipramine的大鼠有顯著的類強迫症行為。而意外的是，SAPAP3在紋狀體的傳訊核糖核酸及蛋白質表現量並沒有因為新生暴露clomipramine的處理而有顯著性的改變。此外，PSD-95、5-HT1B受體和STEP蛋白在眼窩前額皮質和紋狀體中的蛋白質表現量也沒有因為新生投予clomipramine而改變。有趣的是，給予高頻電刺激後，新生暴露clomipramine的大鼠在紋狀體呈現了比較強的突觸增益現象。這些結果顯示雖然新生暴露clomipramine的大鼠會誘發多重類強迫症症狀，但在這個大鼠模式中，其紋狀體的SAPAP3表現沒有受損。

Synapse-associated protein 90/PSD-95-associated protein 3 (SAPAP3) is a postsynaptic scaffolding protein that is highly expressed in striatal excitatory synapses. Previous studies have reported that Sapap3-/- mice exhibit compulsive-like behaviors and dysfunction of cortico-striatal synaptic transmission. Interestingly, a recent study reported that neonatal treatment with the tricyclic antidepressant clomipramine may produce multiple behavioral symptoms in adult rats that are consistent with an obsessive-compulsive disorder (OCD)-like profile in animals. However, the neurobiological basis of this novel model of OCD remains unclear. Thus, the objective of this proposal is to evaluate the role of SAPAP3 at cortico-striatal synapses in neonatal clomipramine treatment-induced OCD-like model. We found that clomipramine exposure in immature rat pups between days 9 and 16 twice daily produced significant OCD-like behaviors in early adulthood by using behavioral tests such as spontaneous grooming behavior, marble burying, light-dark test, and elevated plus maze. To our surprise, both the mRNA and protein levels of SAPAP3 in the striatum were not significantly altered by neonatal clomipramine treatment. In addition, the expression of PSD-95, 5-HT1B receptor and STEP proteins in both the orbitofrontal cortex and the striatum were not altered by neonatal clomipramine treatment. Interestingly, clomipramine-exposed rats show increased high frequency stimulation-induced synaptic potentiation at cortico-striatal synapses. These results suggest that although neonatal clomipramine treatment may induce multiple symptoms consistent OCD-like profile, striatal SAPAP3 remains intact in this model.

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