Wearne Travis A, Parker Lindsay M, Franklin Jane L, Goodchild Ann K, Cornish Jennifer L
Department of Psychology, Faculty of Human Sciences, Centre for Emotional Health, Macquarie University, Sydney, NSW, Australia.
Department of Biomedical Science, Faculty of Medicine and Health Science, Macquarie University, Sydney, NSW, Australia; ARC Center of Excellence for Nanoscale BioPhotonics, Macquarie University, Sydney, NSW, Australia.
Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jul 3;77:42-48. doi: 10.1016/j.pnpbp.2017.03.018. Epub 2017 Mar 27.
Schizophrenia is associated with significant pathophysiological changes to interneurons within the prefrontal cortex (PFC), with mRNA and protein changes associated with the GABA network localized to specific interneuron subtypes. Methamphetamine is a commonly abused psychostimulant that can induce chronic psychosis and symptoms that are similar to schizophrenia, suggesting that chronic METH induced psychosis may be associated with similar brain pathology to schizophrenia in the PFC. The aim of this study, therefore, was to examine mRNA expression of interneuron markers across two regions of the PFC (prelimbic (PRL) and orbitofrontal cortices (OFC)) following METH sensitization, an animal model of METH psychosis. We also studied the association between GABA mRNA expression and interneuronal mRNA expression to identify whether particular changes to the GABA network could be localized to a specific inhibitory cellular phenotype. METH sensitization increased the transcriptional expression of calbindin, calretinin, somatostatin, cholecyctokinin and vasoactive intestinal peptide in the PRL while parvalbumin, calbindin, cholectokinin and vasoactive intestinal peptide were upregulated in the OFC. Based on our previous findings, we also found significant correlations between GAD, GAT and parvalbumin while GAD, GAD and GAT were positively correlated with cholecystokinin in the PRL of METH sensitized rats. Within the OFC, the expression of GABAα1 was positively correlated with somatostatin while GABAα5 was negatively associated with somatostatin and calbindin. These findings suggest that METH sensitization differentially changes the expression of mRNAs encoding for multiple peptides and calcium binding proteins across the PRL and the OFC. Furthermore, these findings support that changes to the GABA network may also occur within specific cell types. These results, therefore, provide the first evidence that METH sensitization mediates differential interneuronal pathology across the PRL and OFC and such changes could have profound consequences on behavior and cognitive output.
精神分裂症与前额叶皮质（PFC）内中间神经元的显著病理生理变化相关，与GABA网络相关的mRNA和蛋白质变化定位于特定的中间神经元亚型。甲基苯丙胺是一种常见的滥用精神兴奋剂，可诱发慢性精神病和类似于精神分裂症的症状，这表明慢性甲基苯丙胺诱发的精神病可能与PFC中与精神分裂症相似的脑病理学有关。因此，本研究的目的是在甲基苯丙胺致敏后，即甲基苯丙胺精神病的动物模型中，检查PFC的两个区域（边缘前区（PRL）和眶额皮质（OFC））中中间神经元标志物的mRNA表达。我们还研究了GABA mRNA表达与中间神经元mRNA表达之间的关联，以确定GABA网络的特定变化是否可定位于特定的抑制性细胞表型。甲基苯丙胺致敏增加了PRL中钙结合蛋白、钙视网膜蛋白、生长抑素、胆囊收缩素和血管活性肠肽的转录表达，而OFC中小白蛋白、钙结合蛋白、胆囊收缩素和血管活性肠肽上调。基于我们之前的研究结果，我们还发现甲基苯丙胺致敏大鼠的PRL中，谷氨酸脱羧酶（GAD）、γ-氨基丁酸转运体（GAT）和小白蛋白之间存在显著相关性，而GAD、GAD和GAT与胆囊收缩素呈正相关。在OFC内，GABAα1的表达与生长抑素呈正相关，而GABAα5与生长抑素和钙结合蛋白呈负相关。这些发现表明，甲基苯丙胺致敏差异性地改变了PRL和OFC中编码多种肽和钙结合蛋白的mRNA表达。此外，这些发现支持GABA网络的变化也可能发生在特定的细胞类型中。因此，这些结果提供了首个证据，表明甲基苯丙胺致敏介导了PRL和OFC之间差异性的中间神经元病理学变化，而这种变化可能对行为和认知输出产生深远影响。
