Chou Shinnyi, Fish Kenneth N, Lewis David A, Sweet Robert A
Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15261.
bioRxiv. 2023 Apr 11:2023.04.11.536217. doi: 10.1101/2023.04.11.536217.
Individuals with schizophrenia are at elevated genetic risks for comorbid cannabis use, and often experience exacerbations of cognitive and psychotic symptoms when exposed to cannabis. These findings have led a number of investigators to examine cannabinoid CB1 receptor (CB1R) alterations in schizophrenia, though with conflicting results. We recently demonstrated the presence of CB1R in both excitatory and inhibitory boutons in the human prefrontal cortex, with differential levels of the receptor between bouton types. We hypothesized that the differential enrichment of CB1R between bouton types - a factor previously unaccounted for when examining CB1R changes in schizophrenia - may resolve prior discrepant reports and increase our insight into the effects of CB1R alterations on the pathophysiology of schizophrenia.
Using co-labeling immunohistochemistry and fluorescent microscopy, we examined total CB1R levels and CB1R levels within excitatory (vGlut1-positive) and inhibitory (vGAT-positive) boutons of prefrontal cortex samples from ten pairs of individuals diagnosed with schizophrenia and non-psychiatric comparisons.
Significantly higher total CB1R levels were found within samples from individuals with schizophrenia. Terminal type-specific analyses identified significantly higher CB1R levels within excitatory boutons in samples from individuals with schizophrenia relative to comparisons. In contrast, CB1R levels within the subset of inhibitory boutons that normally express high CB1R levels (presumptive cholecystokinin neuron boutons) were lower in samples from individuals with schizophrenia relative to comparison samples.
Given CB1R's role in suppressing neurotransmission upon activation, these results suggest an overall shift in excitatory and inhibitory balance regulation toward a net reduction of excitatory activity in schizophrenia.
精神分裂症患者合并使用大麻的遗传风险较高，且接触大麻时常常会出现认知和精神病性症状的加重。这些发现促使许多研究人员研究精神分裂症中大麻素CB1受体（CB1R）的改变，但其结果相互矛盾。我们最近证明了CB1R在人类前额叶皮质的兴奋性和抑制性终扣中均有存在，且终扣类型之间的受体水平存在差异。我们假设终扣类型之间CB1R的差异富集——这是先前在研究精神分裂症中CB1R变化时未考虑的一个因素——可能会解决先前相互矛盾的报告，并增进我们对CB1R改变对精神分裂症病理生理学影响的理解。
我们使用共标记免疫组织化学和荧光显微镜，检查了来自10对被诊断为精神分裂症的个体和非精神疾病对照个体的前额叶皮质样本中总的CB1R水平以及兴奋性（vGlut1阳性）和抑制性（vGAT阳性）终扣内的CB1R水平。
在精神分裂症患者的样本中发现总的CB1R水平显著更高。终扣类型特异性分析发现，与对照组相比，精神分裂症患者样本中兴奋性终扣内的CB1R水平显著更高。相比之下，与对照样本相比，精神分裂症患者样本中通常表达高水平CB1R的抑制性终扣子集（假定胆囊收缩素神经元终扣）内的CB1R水平较低。
鉴于CB1R在激活时抑制神经传递的作用，这些结果表明在精神分裂症中，兴奋性和抑制性平衡调节总体上朝着净减少兴奋性活动的方向转变。
