Department of Bioengineering, Stanford University, Stanford, California, USA.
Nature. 2011 Jul 27;477(7363):171-8. doi: 10.1038/nature10360.
Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.
严重的行为缺陷在精神疾病如自闭症和精神分裂症中被假设是由于神经微电路中兴奋和抑制（E/I 平衡）的细胞平衡升高引起的。这个假设可以统一多种病理生理学和遗传学证据，但还不能进行直接测试。在这里，我们设计并使用了几种新型的光遗传学工具，在自由活动的哺乳动物中进行因果研究，探索相关的电路生理学。我们发现，在小鼠内侧前额叶皮层中升高（而非降低）细胞 E/I 平衡会导致细胞信息处理严重受损，与特定的行为缺陷和 30-80 Hz 范围内高频功率增加有关，这些在人类的临床情况下都有观察到。与 E/I 平衡假说一致，抑制性细胞兴奋性的代偿性升高部分挽救了 E/I 平衡升高引起的社交缺陷。这些结果为严重神经精神疾病相关症状的升高细胞 E/I 平衡假说提供了支持。
