Alshammari T K, Alshammari M A, Nenov M N, Hoxha E, Cambiaghi M, Marcinno A, James T F, Singh P, Labate D, Li J, Meltzer H Y, Sacchetti B, Tempia F, Laezza F
Pharmacology and Toxicology Graduate Program, University of Texas Medical Branch, Galveston, TX, USA.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Transl Psychiatry. 2016 May 10;6(5):e806. doi: 10.1038/tp.2016.66.
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.
认知加工高度依赖于大脑中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。小白蛋白（PV）中间神经元功能减退以及皮质回路中GABA能突触的破坏会导致网络活动失同步，这与包括精神分裂症在内的许多精神疾病中的认知障碍相关。然而，这些复杂表型背后的机制仍知之甚少。在此我们表明，在动物模型中，成纤维细胞生长因子14（Fgf14）的基因缺失，Fgf14是神经元兴奋性和突触传递的调节因子，会导致海马CA1区PV中间神经元丢失，CA1区是认知功能的关键区域。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转运体（VGAT）的表达降低相关，也与CA1抑制性回路破坏、体内γ频率振荡降低和工作记忆受损同时出现。对精神分裂症转录组学的生物信息学分析显示，FGF14与GABA能通路中富集的基因在功能上共同聚类，并且在疾病背景下FGF14、PVALB、GAD67和VGAT的表达呈相关性降低。这些结果表明，Fgf14基因敲除小鼠概括了与人类认知障碍相关的显著分子、细胞、功能和行为特征，FGF14功能丧失可能与精神分裂症等复杂脑部疾病的生物学机制有关。
