Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction.
Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction.
复制标题
DOI：
10.1038/tp.2013.104
复制
发表时间：
2013-12-03
影响因子：
6.8
通讯作者：
Arnsten AF
中科院分区：
文献类型：
--
作者：
Gamo NJ;Duque A;Paspalas CD;Kata A;Fine R;Boven L;Bryan C;Lo T;Anighoro K;Bermudez L;Peng K;Annor A;Raja A;Mansson E;Taylor SR;Patel K;Simen AA;Arnsten AF
最近的遗传学研究已将精神疾病与精神分裂症 1 破坏 (DISC1) 的改变联系起来，DISC1 是一种多功能支架蛋白，通过与磷酸二酯酶 4 (PDE4) 相互作用来调节环磷酸腺苷 (cAMP) 信号传导。压力暴露期间高水平的 cAMP 会损害前额皮质 (PFC) 的功能，而前额皮质是深受精神疾病困扰的区域。由于压力会加重精神疾病，对 DISC1 的基因损伤可能会增加 cAMP 水平，从而使症状恶化。目前的研究检验了大鼠 PFC 中 Disc1 基因的病毒敲除 (KD) 是否会增加对应激引起的 PFC 功能障碍的易感性。大鼠接受空间工作记忆任务训练，然后接受以下输注：(a) 敲低 PFC 中 Disc1 的活性病毒构建体（DISC1 KD 组），(b) 对 Disc1 没有影响的“乱序”构建体（乱序组），或 (c) 减少 PFC 背侧 DISC1 表达的活性构建体（解剖对照组）。将数据与未手术的对照组进行比较。在对正常动物没有影响的轻度约束应激后评估认知表现。 DISC1 KD 大鼠因 1 小时的束缚应激而受损，而乱序组、对照组和解剖对照组不受影响。因此，敲除 PFC 中的 Disc1 可以降低压力诱发的认知功能障碍的阈值，这可能是通过神经网络突触处的 cAMP 信号解除抑制来实现的。这些发现可以解释为什么携带 DISC1 突变的患者可能特别容易受到压力的影响。
Recent genetic studies have linked mental illness to alterations in disrupted in schizophrenia 1 (DISC1), a multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (cAMP) signaling via interactions with phosphodiesterase 4 (PDE4). High levels of cAMP during stress exposure impair function of the prefrontal cortex (PFC), a region gravely afflicted in mental illness. As stress can aggravate mental illness, genetic insults to DISC1 may worsen symptoms by increasing cAMP levels. The current study examined whether viral knockdown (KD) of the Disc1 gene in rat PFC increases susceptibility to stress-induced PFC dysfunction. Rats were trained in a spatial working memory task before receiving infusions of (a) an active viral construct that knocked down Disc1 in PFC (DISC1 KD group), (b) a ‘scrambled' construct that had no effect on Disc1 (Scrambled group), or (c) an active construct that reduced DISC1 expression dorsal to PFC (Anatomical Control group). Data were compared with an unoperated Control group. Cognitive performance was assessed following mild restraint stress that had no effect on normal animals. DISC1 KD rats were impaired by 1 h restraint stress, whereas Scrambled, Control, and Anatomical Control groups were unaffected. Thus, knocking down Disc1 in PFC reduced the threshold for stress-induced cognitive dysfunction, possibly through disinhibited cAMP signaling at neuronal network synapses. These findings may explain why patients with DISC1 mutations may be especially vulnerable to the effects of stress.
登录
查看更多内容
影响因子：
34.7
作者：
Arnsten, Amy F. T.
通讯作者：
Arnsten, Amy F. T.
影响因子：
--
作者：
Blumberg, HP;Leung, HC;Peterson, BS
通讯作者：
Peterson, BS
影响因子：
16.2
作者：
Arnsten AF;Wang MJ;Paspalas CD
通讯作者：
Paspalas CD
影响因子：
1.9
作者：
Gamo, Nao J.;Arnsten, Amy F. T.
通讯作者：
Arnsten, Amy F. T.
影响因子：
--
作者：
Cannon, TD;Hennah, W;Peltonen, L
通讯作者：
Peltonen, L