Institute of Molecular Medicine and Genetics and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912.
J Neurosci. 2013 Sep 18;33(38):15022-31. doi: 10.1523/JNEUROSCI.5833-12.2013.
Endocannabinoids play essential roles in synaptic plasticity; thus, their dysfunction often causes impairments in memory or cognition. However, it is not well understood whether deficits in the endocannabinoid system account for the cognitive symptoms of schizophrenia. Here, we show that endocannabinoid-mediated synaptic regulation is impaired by the prolonged elevation of neuregulin-1, the abnormality of which is a hallmark in many patients with schizophrenia. When rat hippocampal slices were chronically treated with neuregulin-1, the degradation of 2-arachidonoylglycerol (2-AG), one of the major endocannabinoids, was enhanced due to the increased expression of its degradative enzyme, monoacylglycerol lipase. As a result, the time course of depolarization-induced 2-AG signaling was shortened, and the magnitude of 2-AG-dependent long-term depression of inhibitory synapses was reduced. Our study reveals that an alteration in the signaling of 2-AG contributes to hippocampal synaptic dysfunction in a hyper-neuregulin-1 condition and thus provides novel insights into potential schizophrenic therapeutics that target the endocannabinoid system.
内源性大麻素在突触可塑性中发挥着重要作用；因此，它们的功能障碍常导致记忆或认知受损。然而，内源性大麻素系统的缺陷是否导致精神分裂症的认知症状尚不清楚。在这里，我们表明，神经调节素-1的长期升高会损害内源性大麻素介导的突触调节，这种异常是许多精神分裂症患者的一个标志。当大鼠海马切片被神经调节素-1慢性处理时，由于其降解酶单酰基甘油脂肪酶的表达增加，主要内源性大麻素之一 2-花生四烯酸甘油（2-AG）的降解增强。结果，去极化诱导的 2-AG 信号的时间过程缩短，并且 2-AG 依赖性抑制性突触的长时程抑制的幅度减小。我们的研究表明，2-AG 信号的改变有助于在高神经调节素-1条件下的海马突触功能障碍，从而为针对内源性大麻素系统的潜在精神分裂症治疗提供了新的见解。
