Department of Psychiatry, Columbia University, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 62, New York, NY 10032, USA.
Expert Rev Neurother. 2012 Jul;12(7):785-99. doi: 10.1586/ern.12.60.
Complex psychiatric disorders, such as schizophrenia, arise from a combination of genetic, developmental, environmental and social factors. These vulnerabilities can be mitigated by adaptive factors in each of these domains engendering resilience. Modeling resilience in mice using transgenic approaches offers a direct path to intervention, as resilience mutations point directly to therapeutic targets. As prototypes for this approach, we discuss the three mouse models of schizophrenia resilience, all based on modulating glutamatergic synaptic transmission. This motivates the broader development of schizophrenia resilience mouse models independent of specific pathophysiological hypotheses as a strategy for drug discovery. Three guiding validation criteria are presented. A resilience-oriented approach should identify pharmacologically tractable targets and in turn offer new insights into pathophysiological mechanisms.
复杂的精神疾病，如精神分裂症，是由遗传、发育、环境和社会因素共同作用的结果。这些脆弱性可以通过每个领域的适应因素来减轻，从而产生适应力。使用转基因方法在小鼠中模拟适应力为干预提供了直接途径，因为适应力突变直接指向治疗靶点。作为这种方法的原型，我们讨论了三种基于调节谷氨酸能突触传递的精神分裂症适应力小鼠模型。这促使我们在不依赖特定病理生理学假设的情况下，更广泛地开发精神分裂症适应力小鼠模型，作为药物发现的一种策略。提出了三个指导验证标准。以适应力为导向的方法应该确定药物治疗的靶点，并反过来为病理生理学机制提供新的见解。
