Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia.
Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia.
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DOI：
10.1038/tp.2016.66
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发表时间：
2016-05-10
影响因子：
6.8
通讯作者：
Laezza F
中科院分区：
文献类型：
--
作者：
Alshammari TK;Alshammari MA;Nenov MN;Hoxha E;Cambiaghi M;Marcinno A;James TF;Singh P;Labate D;Li J;Meltzer HY;Sacchetti B;Tempia F;Laezza F
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。这些细胞调节主要神经元的兴奋性和突触可塑性，平衡皮质网络的兴奋/抑制基调。小清蛋白 (PV) 中间神经元功能的降低和皮质回路中 GABA 能突触的破坏导致网络活动不同步，与许多精神疾病（包括精神分裂症）的认知障碍相关。然而，这些复杂表型背后的机制仍然知之甚少。在这里，我们表明，在动物模型中，成纤维细胞生长因子 14 (Fgf14)（神经元兴奋性和突触传递的调节因子）的基因缺失会导致 CA1 海马区（认知功能的关键区域）PV 中间神经元的损失。引人注目的是，这种细胞表型与谷氨酸脱羧酶 67 (GAD67) 和囊泡 GABA 转运蛋白 (VGAT) 表达减少相关，也与 CA1 抑制电路破坏、体内伽马频率振荡减少和工作记忆受损相一致。精神分裂症转录组学的生物信息学分析揭示了 FGF14 和 GABA 能途径中富集的基因的功能共聚，以及疾病背景下 FGF14、PVALB、GAD67 和 VGAT 表达的相关降低。这些结果表明，Fgf14−/− 小鼠重现了与人类认知障碍相关的显着分子、细胞、功能和行为特征，并且 FGF14 功能丧失可能与精神分裂症等复杂脑部疾病的生物学有关。
Cognitive processing is highly dependent on the functional integrity of gamma-amino-butyric acid (GABA) interneurons in the brain. These cells regulate excitability and synaptic plasticity of principal neurons balancing the excitatory/inhibitory tone of cortical networks. Reduced function of parvalbumin (PV) interneurons and disruption of GABAergic synapses in the cortical circuitry result in desynchronized network activity associated with cognitive impairment across many psychiatric disorders, including 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 of schizophrenia transcriptomics revealed functional co-clustering of FGF14 and genes enriched within the GABAergic pathway along with correlatively decreased expression of FGF14, 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 as schizophrenia.
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影响因子：
6.8
作者：
Chen HM;DeLong CJ;Bame M;Rajapakse I;Herron TJ;McInnis MG;O'Shea KS
通讯作者：
O'Shea KS
影响因子：
4.7
作者：
Cambiaghi, Marco;Cursi, Marco;Leocani, Letizia
通讯作者：
Leocani, Letizia
影响因子：
5.3
作者：
Alshammari MA;Alshammari TK;Laezza F
通讯作者：
Laezza F
影响因子：
3.7
作者：
Drgon T;Zhang PW;Johnson C;Walther D;Hess J;Nino M;Uhl GR
通讯作者：
Uhl GR
影响因子：
16.2
作者：
Goldfarb, Mitchell;Schoorlemmer, Jon;D'Angelo, Egidio
通讯作者：
D'Angelo, Egidio