Transgenic Mouse Model for Mental Disorders including schizophrenia

我们目前正在研究COMT、Dysbindin、BDNF、ARC、NRG、BAD、KCNH2以及COMT/Dysbindin的基因-基因相互作用。我们已经用转基因小鼠证明了COMT对精神相关行为的影响，包括认知、情绪唤醒、疼痛敏感性和安非他明反应。COMT活动增加是皮质依赖性认知功能障碍的危险因素，但在压力情况下是保护因素，而COMT减少可以增强工作记忆过程，但会导致过度的应激反应。生成的COMT转基因小鼠（过表达人类COMT-val），并将其与含有无效COMT突变的小鼠进行比较。COMT转基因和敲除小鼠模拟了与COMT多态性相关的人类行为的显著方面，并建立了这些关联的生物学验证。我们的COMT模型表明，一个共同的遗传因素可能参与多种以异常认知加工和应激反应为特征的临床疾病，并代表了一种有希望的新动物模型，用于测试认知和应激相关疗法。在这种情况下，需要建立生物验证策略是很重要的。CBDB/GCAP研究人员已经开发出神经影像学方法，在生物学水平上证实基因内和基因间上位性相互作用的临床证据，并将这些发现扩展到淋巴母细胞系和涉及转基因小鼠品系育种的动物模型中的信号传导。

We currently are investigating COMT, Dysbindin, BDNF, ARC, NRG, BAD, KCNH2 and the gene-gene interaction of COMT/Dysbindin. We have demonstrated conclusively with genetically altered mice the effect of COMT on psychiatric relevant behaviors, including on cognition, emotional arousal, pain sensitivity and amphetamine response. Increased COMT activity is a risk factor for cortically dependent cognitive dysfunctions but a protective factor in stressful situations, whereas COMT reduction enhances working memory processes but results in exaggerated stress reactivity. The generated COMT transgenic mice (overexpressing a human COMT-val), and compared them with mice containing a null COMT mutation. COMT transgenic and knock-out mice mimicked salient aspects of human behaviors associated with COMT polymorphisms, and established the biologic validation of these associations. Our COMT model reifies that a common genetic factor can be involved in diverse clinical disorders characterized by abnormal cognitive processing and stress reactivity and represents a promising new animal model for testing cognitive and stress related therapies. In this context, the need for an established strategy for biological validation is important. CBDB/GCAP investigators have developed neuroimaging methods to confirm at a biological level clinical evidence of epistatic interactions within genes and between genes and have extended these findings to signaling within lymphoblast cell lines and in animal models involving breeding of genetically altered mouse strains. Our transgenic mice overexpressing human COMT-val (Val-tg) was compared with mice without a functional COMT and normal mice which contain COMT-leu. Increased COMT activity in Val-tg mice resulted in impaired attentional set shifting abilities, and working and recognition memory. There was no change in acquisition or reversal learning. COMT Val-tg mice also showed recognition memory deficits. However, acute treatment with amphetamine, which increases dopamine levels, restored recognition memory performance in COMT Val-tg mice but worsened performance control. Despite the COMT genotype effects on working memory processes, COMT Val-tg mice showed normal performance in tasks involving a regularly repeated sequence of events rather than trial-specific experience. These results highlight the COMT gene as a critical factor in the regulation of executive memory processes. With regards to environmental stressors, COMT null mice ( -/-) were the best performers under low stress conditions, whereas COMT heterozygous mice (+/-) performed best under challenging conditions. It appears that mild uncontrolled stress impairs PFC working memory functions in human and animals. We have demonstrated that increased COMT activity is a risk factor for cortically dependent cognitive dysfunctions but a protective factor when under stress, whereas COMT reduction enhances working memory processes but results in exaggerated stress reactions. The COMT transgenic and knock-out mice show notable aspects of human behaviors associated with COMT mutations and establish biologic validity of these associations. Our COMT mouse model establishes that a common genetic factor can be involved in diverse clinical disorders characterized by abnormal cognitive processing and reaction to stress which represents a promising new animal model for testing cognitive and stress related therapies. Finally, these results demonstrate an intriguing functional trade-off between genetic variation that concurrently results in more efficient cognitive behaviors and less adaptive affective behaviors.