Dienel Samuel J, Enwright John F, Hoftman Gil D, Lewis David A
Medical Scientist Training Program, University of Pittsburgh, United States of America; Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, United States of America; Center for the Neural Basis of Cognition, Carnegie Mellon University, United States of America; Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, United States of America.
Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, United States of America.
Schizophr Res. 2020 Mar;217:86-94. doi: 10.1016/j.schres.2019.06.003. Epub 2019 Jul 8.
Cognitive dysfunction in individuals with schizophrenia is thought to reflect, at least in part, altered levels of excitatory and inhibitory neurotransmission in the dorsolateral prefrontal cortex (DLPFC). Studies of the postmortem human brain allow for interrogation of the disease-related alterations in markers of excitatory and inhibitory neurotransmission at different levels of anatomical resolution. Here, we re-analyzed six published datasets from postmortem studies of schizophrenia to assess molecular markers of glutamate and GABA neurotransmission in the DLPFC at three levels of anatomical resolution: 1) total cortical gray matter, 2) gray matter restricted to layer 3, and 3) a layer 3 local circuit composed of excitatory pyramidal cells and inhibitory, parvalbumin-containing, GABA neurons. We formulated composite measures of glutamate and GABA neurotransmission from z-scores of key transcripts that regulate these functions. Relative to unaffected comparison subjects, the composite glutamate measure was higher in schizophrenia subjects in total gray matter homogenates but lower in samples restricted to layer 3 or the layer 3 local circuit. The composite index of GABA neurotransmission did not differ between subject groups in total gray matter homogenates but was lower in schizophrenia subjects in layer 3 and lower still in the local layer 3 circuit. These findings suggest that the balance of excitation and inhibition in the DLPFC of schizophrenia subjects differs depending on the level of anatomical resolution studied, highlighting the importance of layer- and cell type-specific studies to understand disease-related alterations in cortical circuitry.
精神分裂症患者的认知功能障碍被认为至少部分反映了背外侧前额叶皮质（DLPFC）中兴奋性和抑制性神经传递水平的改变。对死后人类大脑的研究有助于在不同解剖分辨率水平上探究与疾病相关的兴奋性和抑制性神经传递标志物的改变。在这里，我们重新分析了六个已发表的精神分裂症死后研究数据集，以评估DLPFC中谷氨酸和GABA神经传递的分子标志物，解剖分辨率分为三个水平：1）整个皮质灰质；2）仅限于第3层的灰质；3）由兴奋性锥体细胞和抑制性含小白蛋白的GABA神经元组成的第3层局部回路。我们根据调节这些功能的关键转录本的z分数制定了谷氨酸和GABA神经传递的综合测量指标。与未受影响的对照受试者相比，精神分裂症受试者在整个灰质匀浆中的谷氨酸综合测量值较高，但在仅限于第3层或第3层局部回路的样本中较低。GABA神经传递的综合指数在整个灰质匀浆的受试者组之间没有差异，但在第3层的精神分裂症受试者中较低，在第3层局部回路中更低。这些发现表明，精神分裂症受试者DLPFC中的兴奋与抑制平衡因所研究的解剖分辨率水平而异，突出了层特异性和细胞类型特异性研究对于理解皮质回路中与疾病相关改变的重要性。
