Department of Psychiatry, Columbia University, New York, NY 10032, USA.
Schizophr Bull. 2009 Nov;35(6):1037-44. doi: 10.1093/schbul/sbp114. Epub 2009 Oct 14.
We describe here a coordinated brain imaging and animal models approach in which we have shown that the hippocampal CA1 region is a principal node in schizophrenia pathogenesis and have identified a novel treatment approach to the disorder based on inhibition of glutamate release. To identify biomarkers, we have focused on the putative prodromal period, typically lasting a few years, preceding the first onset of psychosis. About one-third of a high-risk cohort followed prospectively for 2.5 years will progress to threshold psychosis, making it possible to perform a relatively short prospective study. We have utilized a technological development in functional imaging techniques in which we measure cerebral blood volume (CBV), which allows for interrogation of subregions of the brain in the basal state at submillimeter resolution. Measurements of CBV in schizophrenia as well as in high-risk or prodromal stages can then pinpoint brain subregions differentially targeted during the earliest stages of the disorder. Our data suggest that the CA1 subfield of the hippocampal formation is most consistently implicated across disease stages, identifying a putative biomarker suitable for guiding drug development. Our studies in transgenic mice mutant in the glutamate synthetic enzyme glutaminase support the hypothesis that CA1 hyperfunction is due to altered glutamatergic neurotransmission. As a proof of principle, the glutaminase-deficient mice suggest that pharmacotherapies that reduce glutamatergic neurotransmission in the CA1 subfield may be a uniquely effective therapeutic strategy in schizophrenia and preventative in prodromal stages of the disorder.
我们在这里描述了一种协调的脑成像和动物模型方法，通过该方法我们已经表明海马 CA1 区域是精神分裂症发病机制的主要节点，并基于抑制谷氨酸释放确定了一种针对该疾病的新的治疗方法。为了确定生物标志物，我们专注于假定的前驱期，通常持续几年，在前精神病发作之前。大约三分之一的前瞻性随访 2.5 年的高风险队列将进展到阈值精神病，从而有可能进行相对较短的前瞻性研究。我们利用了功能成像技术的技术发展，在该技术中我们测量脑血容量（CBV），这允许以亚毫米分辨率询问基底状态下的脑区的亚区。精神分裂症以及高风险或前驱期的 CBV 测量可以精确定位在疾病早期阶段靶向的脑亚区。我们的数据表明，海马结构的 CA1 亚区在整个疾病阶段最一致地涉及，确定了适合指导药物开发的潜在生物标志物。我们在谷氨酸合成酶谷氨酸酶突变的转基因小鼠中的研究支持 CA1 功能亢进是由于谷氨酸能神经传递改变的假设。作为原理证明，缺乏谷氨酰胺酶的小鼠表明，减少 CA1 亚区谷氨酸能神经传递的药物治疗可能是精神分裂症的一种独特有效的治疗策略，并且在疾病的前驱期具有预防作用。
