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

T. K. Alshammari, M. A. Alshammari, M. N. Nenov, E. Hoxha, M. Cambiaghi, A. Marcinno, T. F. James, P. Singh, D. Labate, J. Li, H. Y. Meltzer, B. Sacchetti, F. Tempia, F. Laezza

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Article numbere806
JournalTranslational psychiatry
Volume6
Issue number5
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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    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. (2016). Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia. Translational psychiatry, 6(5), [e806]. https://doi.org/10.1038/tp.2016.66