Coiled-coil and C2 domain containing 1A (CC2D1A) 是一種會廣泛表現於人體各種組織中的蛋白質，最初是在研究NF-κB (nuclear factor-κB) 訊息傳遞路徑時被發現的，其被證明可以作為NF-κB訊息傳遞路徑中的活化劑。此後，CC2D1A也被證實其可作為信號蛋白的角色，參與在cAMP (cycle adenosine monophosphate)–PKA (cAMP-dependent protein kinase) 和PDK1 (phosphoinositide-dependent protein kinase-1)/Akt (protein kinase B) 的訊息傳遞路徑中。其亦可作為第二型多巴胺受體D2R與第1A型血清素受體5-HT1A R的轉錄抑制因子。在近年的臨床研究中發現，憂鬱症患者於前額葉皮質 (prefrontal cortex) 區域中的CC2D1A有失調的情形，而在非症候群型智能障礙 (non-syndromic intellectual disability, NSID) 的患者身上也看到Cc2d1a基因產生變異，顯示CC2D1A的失調在憂鬱症以及智能障礙的疾病中可能扮演著重要的角色，然而對於作用的生物機制仍然不清楚。前額葉皮質為大腦中主要負責認知、執行、決策、空間工作記憶 (spatial working memory) 以及情緒的管理等功能。在前額葉皮質區受傷的病患中觀察到，會產生類似阿茲海默症 (Alzheimer’s disease) 與思覺失調症 (schizophrenia) 等認知功能的缺陷。另外，憂鬱症患者的腹側前額葉皮質 (ventromedial prefrontal cortex) 中也有異常活化的情形被發現。因此，在本研究中我們利用條件性剔除Cc2d1a小鼠以探討CC2D1A在內側前額葉皮質的神經元中所扮演的角色。在我們的研究中發現，CC2D1A蛋白質在內側前額葉皮質中於胚胎時期及以出生後第十四天起，為其表現量較高的時期，並且會廣泛的表現在不同種類的神經元中。在利用Cre-loxP基因工程系統，條件性剔除掉興奮性神經元的Cc2d1a基因後，發現條件性剔除Cc2d1a小鼠相較於野生型小鼠，在認知功能的表現上明顯變差，但在類憂鬱的相關行為測試中則沒有差異。而專一性的剔除內側前額葉皮質中興奮性神經元Cc2d1a小鼠在空間工作記憶與新奇事物辨識試驗 (novel object recognition test) 中的表現上也較差。在全細胞電氣生理學紀錄的結果中觀察到，條件性剔除Cc2d1a小鼠在內側前額皮質神經元上的NMDA受體的組成提高，同時，在西方點墨法中也看到GluN2A有顯著的增加，而在mRNA的表現量上則看到5-HT1A R、ANKK1、BDNF exon1及exon9有顯著的下降。在神經元的型態上我們發現，條件性剔除Cc2d1a小鼠在內側前額葉皮質中的尖端樹突分支程度有減少現象，而興奮性與抑制性的神經突觸則都有增加的情形。此外，我們檢測了被認為會影響認知功能表現的三條訊息傳遞路徑，包括cAMP-PKA、PDK1/Akt以及NF-κB，而從實驗結果中看到，條件性剔除Cc2d1a小鼠的內側前額葉皮質在這三條路徑的表現上，與野生型小鼠相比並沒有明顯差異。綜合以上實驗結果，我們推測條件性剔除Cc2d1a小鼠在認知功能試驗中的表現變差，可能是由於BDNF的表現量下降，影響了神經元的型態及功能所導致。本研究更加確定CC2D1A在認知功能上所扮演的重要角色。

CC2D1A is originally identified as a nuclear factor-κB activator of human gene. It is highly expressed in human tissues, including the brain, stomach, small intestine, nasopharynx, gallbladder and testis. Recent genetic and biochemical evidence strongly suggests that CC2D1A functions as a transcriptional repressor of neuronal 5-HT1A receptor and D2 receptor genes. Additionally, CC2D1A can also function as a signaling protein in cAMP-PKA, PDK1/Akt signaling pathways. Human studies have shown that CC2D1A dysregulation may contribute to the development of major depression and non-syndromic intellectual disability. However, the precise mechanisms by which CC2D1A regulates intellectual and psychological functions remain elusive. Medial prefrontal cortex has been considered as the integration part of brain, which regulates cognitive function, executive function, spatial working memory, as well as emotional management. The clinical research have found that those patient whose prefrontal cortex were injured showed recognition impaired, which is similar to Alzheimer’s disease and schizophrenia. Also, other clinical research showed hyperactivity of ventromedial prefrontal cortex in patient with depression. Here, we examine the role of CC2D1A in neuronal function of the mPFC. We found that CC2D1A is widely expressed in different neuronal cells in mPFC, and its protein expression in mouse mPFC tissue lysates was relatively high during the embryonic stage, and remained constant in adulthood. Genetic deletion of Cc2d1a (Cc2d1a-/-) from excitatory neurons leads to impaired performance in recognition task, and the complexity of apical dendrite is decreased. In addition, Cc2d1a-/- mice showed an increase in the NMDA/AMPA ratio. Furthermore, significant increases of NMDA receptor subunit GluN2A protein, as well as NLGN1 and NLGN2 protein expression and decreases 5-HT1A receptor expression were observed in the mPFC from CC2D1A-/- mice compared to those from wild-type mice. Also, notable decreases of 5-HT1AR, ANKK1, BDNF exon1 and exon9 mRNA levels were observed in the mPFC from Cc2d1a-/- mice compared to wild-type mice. According to our study, we proposed that decreased BDNF affect dendritic morphology, which lead to cognitive function impaired in Cc2d1a-/- mice. Our findings demonstrate a novel role for CC2D1A in regulating mPFC-dependent cognitive functions.

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