Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia

被引:28
作者
Alshammari, T. K. [1 ,2 ,3 ]
Alshammari, M. A. [1 ,2 ,3 ]
Nenov, M. N. [2 ]
Hoxha, E. [4 ,5 ]
Cambiaghi, M. [5 ]
Marcinno, A. [4 ]
James, T. F. [5 ]
Singh, P. [6 ]
Labate, D. [6 ]
Li, J. [7 ]
Meltzer, H. Y. [7 ]
Sacchetti, B. [5 ]
Tempia, F. [2 ,4 ,5 ]
Laezza, F. [2 ,8 ,9 ]
机构
[1] Univ Texas Med Branch, Pharmacol & Toxicol Grad Program, Galveston, TX 77555 USA
[2] Univ Texas Med Branch, Dept Pharmacol & Toxicol, 301 Univ Blvd, Galveston, TX 77555 USA
[3] King Saud Univ, King Saud Univ Grad Studies Abroad Program, Riyadh, Saudi Arabia
[4] Neurosci Inst Cavalieri Ottolenghi, Turin, Italy
[5] Univ Turin, Dept Neurosci, Turin, Italy
[6] Univ Houston, Dept Math, Houston, TX 77204 USA
[7] Northwestern Univ, Dept Psychiat & Behav Sci, Feinberg Sch Med, Chicago, IL 60611 USA
[8] Univ Texas Med Branch, Mitchell Ctr Neurodegenerat Dis, Galveston, TX 77555 USA
[9] Univ Texas Med Branch, Addict Res Ctr, Galveston, TX 77555 USA
基金
美国国家科学基金会;
关键词
GENOME-WIDE ASSOCIATION; PROTEIN-PROTEIN INTERACTIONS; CEREBELLAR PURKINJE NEURONS; PLURIPOTENT STEM-CELLS; GATED SODIUM-CHANNELS; ACID DECARBOXYLASE 67; PRIMARY VISUAL-CORTEX; GAMMA OSCILLATIONS; PREFRONTAL CORTEX; BIPOLAR DISORDER;
D O I
10.1038/tp.2016.66
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
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.
引用
收藏
页码:e806 / e806
页数:10
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