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.

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

“…In mice, targeted disruption of FGF14 produces severe ataxia, paroxysmal dystonia, and cognitive impairment (Wang et al, 2002; Wozniak et al, 2007), with neurons that exhibit severe impairments in synaptic transmission and plasticity, and neuronal excitability (Alshammari et al, 2016a,b; Xiao et al, 2007; Wozniak et al, 2007). Significantly, the assembly and trafficking of FGF14 itself is controlled via a GSK–3 dependent signaling pathway that may critically regulate excitability through PPI at the level of the Nav complex (Hsu et al, 2015; Shavkunov et al, 2013).…”

“…First identified as the source of the hereditary spinocerebellar ataxia 27 (Brusse et al, 2006; van Swieten et al, 2003), a debilitating childhood-onset condition characterized by postural tremor, slowly progressive ataxia, and cognitive deficits, SNPs in fgf14 have been identified recently in a genome-wide study performed on a Dutchmajor depressive disorder cohort (Verbeek et al, 2012). Additionally, copy variants of fgf14 have been found in a pediatric population admitted for recurrent unprovoked seizures (Olson et al, 2014), IGF-1 induced neuroprotection against oxidative stresses is accompanied by downregulation of fgf14 (Genis et al, 2014), and correlative changes in FGF14 and markers of GABAergic inhibitory transmission have been found in transcriptomics from post-mortem schizophrenia patients (Alshammari et al, 2016b). …”

“…Animal studies furthering investigating the role of FGF14 in the brain will be important translational models to elucidate this emerging role of FGF14 in humans afflicted with AD and other numerous brain disorders, including schizophrenia (Alshammari et al, 2016b; Gadelha et al, 2012; Brzustowicz et al, 1999; Need et al, 2009) and major depressive disorder (Verbeek et al, 2012), to which critical links with FGF14 have been found.…”

“…In humans, a naturally occurring F145S mutation in the FGF14 gene is implicated in the development of spinocerebellar ataxia 27 (SCA27), a severe motor and cognitive neurodegenerative disorder (Laezza et al, 2009; Brusse et al, 2006; Wozniak et al, 2007; Coebergh et al, 2014), and SNPs in the Fgf14 gene have been associated with depression and schizophrenia (Hsu et al, 2014; Verbeek et al, 2012; Rodriguez-Murillo et al, 2014; Di Re et al, 2017). Recent transcriptomics studies from human post-mortem brains identify FGF14 as a new schizophrenia risk gene, a finding that is corroborated by fgf14 −/− mice which exhibit phenotypes including changes in network activity, decreased gamma frequency, and cognitive impairments that mimic the human disease (Alshammari et al, 2016b). In addition, studies performed on the Alzheimer's Disease Neuroimaging Initiative (ADNI) WGS data have shown SNP rs17502999 in Fgf14 to be significantly associated with entorhinal cortex volume change in AD (Di Re et al, 2017; Yang et al, 2015).…”

“…Among these, fibroblast growth factor 14 (FGF14) stands out for its specific modulatory roles on neuronal Nav channels. Recent studies highlight the importance of FGF14, a multivalent accessory protein of the Nav channel, in animal as well as human studies (Hsu et al, 2015, 2016; James et al, 2015; Ali et al, 2016; Alshammari et al, 2016a, b, c; Tempia et al, 2015; Ali et al, 2014; Shavkunov et al, 2013). Through direct monomeric binding to the Nav channel C-terminal tail, FGF14 forms a complex with the channel that is required for proper gating, expression and trafficking of the channel to the AIS as well as the control of neuronal excitability (Ali et al, 2014, 2016; Alshammari et al, 2016a; Laezza et al, 2007, 2009; Lou et al, 2005; Wang et al, 2000, 2002; Xiao et al, 2007; Goetz et al, 2009).…”