Original Article

Citation: Translational Psychiatry (2016) 6, e806; doi:10.1038/tp.2016.66
Published online 10 May 2016

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

T K Alshammari1,2,3,10, M A Alshammari1,2,3,10, M N Nenov2, E Hoxha4,5, M Cambiaghi5, A Marcinno4, T F James5, P Singh6, D Labate6, J Li7,8, H Y Meltzer7, B Sacchetti5, F Tempia2,4,5 and F Laezza2,8,9

  1. 1Pharmacology and Toxicology Graduate Program, University of Texas Medical Branch, Galveston, TX, USA
  2. 2Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
  3. 3King Saud University Graduate Studies Abroad Program, King Saud University, Riyadh, Saudi Arabia
  4. 4Neuroscience Institute Cavalieri Ottolenghi, Turin, Italy
  5. 5Department of Neuroscience, University of Torino, Turin, Italy
  6. 6Department of Mathematics, University of Houston, Houston, TX, USA
  7. 7Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  8. 8Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA
  9. 9Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA

Correspondence: Dr F Laezza, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA. E-mail: felaezza@utmb.edu

10These authors contributed equally to this work.

Received 30 September 2015; Revised 25 February 2016; Accepted 5 March 2016



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.