| 1 | 摩尔。精神病学2011年1月16日：37-58 |
|---|---|
| PMID | 19935739 |
| 标题 | Identification of blood biomarkers for psychosis using convergent functional genomics. |
| 抽象的 | There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients withschizophrenia以及相关的疾病，并在抽血时收集了表型信息，然后与其他人类和动物模型的证据线交叉匹配数据。在我们的幻觉候选血液生物标志物列表中，我们在高幻觉状态（FN1，RHOBTB3，ALDH1L1，MPP3）的表达中有四个基因降低，而高幻觉状态的三个基因（ARHGEF9，PHLDA1，S100A6）中的三个基因增加。所有这些基因都有先前证明在schizophrenia病人。在我们为妄想的候选血液生物标志物列表的顶部，在高妄想状态（例如DRD2，APOE，SCAMP1，FN1，IDH1，ALDH1L1）中，我们的表达降低了15个基因，而在高妄想状态中的16个基因（例如作为NRG1，Egr1，PVALB, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression inschizophrenia病人。Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such asschizophrenia. |
| SCZ关键字 | schizophrenia |
| 2 | 摩尔。Psychiatry 2015 Dec 20: 1499-507 |
| PMID | 25623945 |
| 标题 | Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. |
| 抽象的 | Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark ofschizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control ofPVALBbacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in ?-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that thePVALB/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission fromPVALB+神经元主要影响与恐惧和新颖性寻求新颖性有关的行为领域，这些改变可能与观察到的行为表型有关schizophrenia. |
| SCZ关键字 | schizophrenia |
| 3 | 神经科学2016年5月321日：236-45 |
| PMID | 26318335 |
| 标题 | Transgenic labeling of parvalbumin-expressing neurons with tdTomato. |
| 抽象的 | Parvalbumin (PVALB)-expressing fast-spiking interneurons subserve important roles in many brain regions by modulating circuit function and dysfunction of these neurons is strongly implicated in neuropsychiatric disorders includingschizophrenia和自闭症。促进研究PVALBneuron function we need to be able to identifyPVALBneurons in vivo. We have generated a bacterial artificial chromosome (BAC) transgenic mouse line expressing the red fluorophore tdTomato under the control of endogenous regulatory elements of thePVALB基因基因座（JAX＃027395）。我们证明TDTOMATO转基因相对于内生忠实地表达PVALBexpression throughout the brain. Furthermore, targeted patch clamp recordings confirm that the labeled populations in neocortex, striatum, and hippocampus are fast-spiking interneurons based on intrinsic properties. This new transgenic mouse line provides a useful tool to studyPVALBneuron function in the normal brain as well as in mouse models of psychiatric disease. |
| SCZ关键字 | schizophrenia |
| 4 | Transl Psychiatry 2016 -1 6: e806 |
| PMID | 27163207 |
| 标题 | Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia. |
| 抽象的 | 认知处理高度依赖于大脑中γ-氨基丁酸（GABA）中间神经元的功能完整性。这些细胞调节主神经元的兴奋性和突触可塑性，平衡皮质网络的兴奋性/抑制性张力。白蛋白（PV）中间神经元的功能降低和皮质回路中GABA能突触的破坏导致与许多精神疾病的认知障碍相关的脱节网络活动，包括许多精神疾病schizophrenia. However, the mechanisms underlying these complex phenotypes are still poorly understood. Here we show that in animal models, genetic deletion of fibroblast growth factor 14 (Fgf14), a regulator of neuronal excitability and synaptic transmission, leads to loss of PV interneurons in the CA1 hippocampal region, a critical area for cognitive function. Strikingly, this cellular phenotype associates with decreased expression of glutamic acid decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) and also coincides with disrupted CA1 inhibitory circuitry, reduced in vivo gamma frequency oscillations and impaired working memory. Bioinformatics analysis ofschizophrenia转录组学揭示了FGF14和富含GABA能途径中的基因的功能共聚类，以及FGF14的表达相关的相关表达，PVALB, GAD67 and VGAT in the disease context. These results indicate that Fgf14(-/-) mice recapitulate salient molecular, cellular, functional and behavioral features associated with human cognitive impairment, and FGF14 loss of function might be associated with the biology of complex brain disorders such asschizophrenia. |
| SCZ关键字 | schizophrenia |