title: Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia.
abstract: 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.
authors.affiliation: 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.|King Saud University Graduate Studies Abroad Program, King Saud University, Riyadh, Saudi Arabia.
authors.forename: T K
authors.initials: TK
authors.lastname: Alshammari
authors.affiliation: 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.|King Saud University Graduate Studies Abroad Program, King Saud University, Riyadh, Saudi Arabia.
authors.forename: M A
authors.initials: MA
authors.lastname: Alshammari
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Nenov
authors.affiliation: Neuroscience Institute Cavalieri Ottolenghi, Turin, Italy.|Department of Neuroscience, University of Torino, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Hoxha
authors.affiliation: Department of Neuroscience, University of Torino, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cambiaghi
authors.affiliation: Neuroscience Institute Cavalieri Ottolenghi, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Marcinno
authors.affiliation: Department of Neuroscience, University of Torino, Turin, Italy.
authors.forename: T F
authors.initials: TF
authors.lastname: James
authors.affiliation: Department of Mathematics, University of Houston, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Mathematics, University of Houston, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Labate
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: H Y
authors.initials: HY
authors.lastname: Meltzer
authors.affiliation: Department of Neuroscience, University of Torino, Turin, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Sacchetti
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.|Neuroscience Institute Cavalieri Ottolenghi, Turin, Italy.|Department of Neuroscience, University of Torino, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Tempia
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.|Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA.|Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: Laezza
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D005346:Fibroblast Growth Factors / Q000235:genetics*; D065818:Gamma Rhythm / Q000502:physiology; D017353:Gene Deletion; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007395:Interneurons / Q000473:pathology; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D010320:Parvalbumins / Q000378:metabolism; D010641:Phenotype; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D012565:Schizophrenic Psychology; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D010320:Parvalbumins; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1