Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3β (GSK3β) and voltage-gated Na channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions-models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3β and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6 by GSK3β. A GSK3β-Nav1.6 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.

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.

The axonal initial segment (AIS) is the subcellular compartment required for initiation of the action potential in neurons. Scaffolding and regulatory proteins at the AIS cluster with ion channels ensuring the integrity of electrical signaling. Interference with the configuration of this protein network can lead to profound effects on neuronal polarity, excitability, cell-to-cell connectivity and brain circuit plasticity. As such, the ability to visualize AIS components with precision provides an invaluable opportunity for parsing out key molecular determinants of neuronal function. Fluorescence-based immunolabeling is a sensitive method for morphological and molecular characterization of fine structures in neurons. Yet, even when combined with confocal microscopy, detection of AIS elements with immunofluorescence has been limited by the loss of antigenicity caused by fixative materials. This technical barrier has posed significant limitations in detecting AIS components alone or in combination with other markers. Here, we designed improved protocols targeted to confocal immunofluorescence detection of the AIS marker fibroblast growth factor 14 (FGF14) in combination with the cytoskeletal-associated protein Ankyrin-G, the scaffolding protein βIV-spectrin, voltage-gated Na+ (Nav) channels (especially the Nav1.6 isoform) and critical cell type-specific neuronal markers such as parvalbumin, calbindin, and NeuN in the mouse brain. Notably, we demonstrate that intracardiac perfusion of animals with a commercially available solution containing 1% formaldehyde and 0.5% methanol, followed by brief fixation with cold acetone is an optimal and sensitive protocol for FGF14 and other AIS marker detection that guarantees excellent tissue integrity. With variations in the procedure, we also significantly improved the detection of Nav1.6, a Nav isoform known for its fixative-sensitivity. Overall, this study provides an ensemble of immunohistochemical recipes that permit excellent staining of otherwise invisible molecules within well-preserved tissue architecture. While improving the specific investigation of AIS physiology and cell biology, our thorough study can also serve as a roadmap for optimizing immunodetection of other fixative-sensitive proteins expanding the repertoire of enabling methods for brain studies.

Genetically inherited mutations in the fibroblast growth factor 14 (FGF14) gene lead to spinocerebellar ataxia type 27 (SCA27), an autosomal dominant disorder characterized by heterogeneous motor and cognitive impairments. Consistently, genetic deletion of Fgf14 in Fgf14−/− mice recapitulates salient features of the SCA27 human disease. In vitro molecular studies in cultured neurons indicate that the FGF14F145S SCA27 allele acts as a dominant negative mutant suppressing the FGF14 wild type function and resulting in inhibition of voltage-gated Na+ and Ca2+ channels. To gain insights in the cerebellar deficits in the animal model of the human disease, we applied whole-cell voltage-clamp in the acute cerebellar slice preparation to examine the properties of parallel fibers (PF) to Purkinje neuron synapses in Fgf14−/− mice and wild type littermates. We found that the AMPA receptor-mediated excitatory postsynaptic currents evoked by PF stimulation (PF-EPSCs) were significantly reduced in Fgf14−/− animals, while short-term plasticity, measured as paired-pulse facilitation (PPF), was enhanced. Measuring Sr2+-induced release of quanta from stimulated synapses, we found that the size of the PF-EPSCs was unchanged, ruling out a postsynaptic deficit. This phenotype was corroborated by decreased expression of VGLUT1, a specific presynaptic marker at PF-Purkinje neuron synapses. We next examined the mGluR1 receptor-induced response (mGluR1-EPSC) that under normal conditions requires a gradual build-up of glutamate concentration in the synaptic cleft, and found no changes in these responses in Fgf14−/− mice. These results provide evidence of a critical role of FGF14 in maintaining presynaptic function at PF-Purkinje neuron synapses highlighting critical target mechanisms to recapitulate the complexity of the SCA27 disease.

Adult neurogenesis, the production of mature neurons from progenitor cells in the adult mammalian brain, is linked to the etiology of neurodegenerative and psychiatric disorders. However, a thorough understanding of the molecular elements at the base of adult neurogenesis remains elusive. Here, we provide evidence for a previously undescribed function of fibroblast growth factor 14 (FGF14), a brain disease-associated factor that controls neuronal excitability and synaptic plasticity, in regulating adult neurogenesis in the dentate gyrus (DG). We found that FGF14 is dynamically expressed in restricted subtypes of Sex Determining Region Y-Box 2 (Sox2) positive and doublecortin (DCX) positive neural progenitors in the DG. BrdU incorporation studies and confocal imaging revealed that genetic deletion of Fgf14 in Fgf14−/− mice leads to a significant change in the proportion of proliferating, and immature and mature newly born adult granule cells. This results in an increase in the late immature and early mature population of DCX and calretinin (CR) positive neurons. Electrophysiological extracellular field recordings showed reduced minimal threshold response and impaired paired-pulse facilitation at the perforant path to DG inputs in Fgf14−/− compared to Fgf14+/+ mice, supporting disrupted synaptic connectivity as a correlative read-out to impaired neurogenesis. These new insights into the biology of FGF14 in neurogenesis shed light into the signaling pathways associated with disrupted functions in complex brain diseases.

Introduction: Due to the diversity of reports and on the rates of medications errors (MEs) in Saudi Arabia, we performed the first meta-analysis to determine the rate of medications errors in Saudi Arabia using meta-analysis in the hospital settings. Methods: We conducted a systematic literature search through August 2019 using PubMed, EMBASE, CINAHL, PsycINFO, and Google Scholar to identify all observational studies conducted in hospital settings in Saudi Arabia that reported the rate of MEs. A random-effects models were used to calculate overall MEs, as well as prescribing, dispensing, and administration error rates. The I 2 statistics were used to analyze heterogeneity. Results: Sixteen articles were included in this search. The total incidence of MEs in Saudi Arabia hospitals was estimated at 44.4%. Prescribing errors, dispensing errors, and adminstration errors incidents represent 40.2%, 28.2%, and 34.5% out of the total number of reported MEs, respectively. However, between-study heterogeneity was also generally found to be >90% (I-squared statistic). Conclusions: This study demonstrates the MEs common in health facilities. Additional efforts in the field are needed to improve medication management systems in order to prevent patient harm incidents.

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Paucar M, Lundin J, Alshammari T, Bergendal Å, Lindefeldt M, Alshammari M, Solders G, Di Re J, Savitcheva I, Granberg T, Laezza F, Iwarsson E, Svenningsson P (Karolinska Institutet; Karolinska University Hospital; Astrid Lindgren’s Hospital, Stockholm, Sweden; The University of Texas Medical Branch, Galveston, TX, USA; King Saud University, Riyadh, Saudi Arabia). Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27. Objective. The goal of this study was to characterize a Swedish family with members affected by spinocerebellar ataxia 27 (SCA27), a rare autosomal dominant disease caused by mutations in fibroblast growth factor 14 ( FGF14 ). Despite normal structural neuroimaging, psychiatric manifestations and intellectual disability are part of the SCA27 phenotype raising the need for functional neuroimaging. Here, we used clinical assessments, structural and functional neuroimaging to characterize these new SCA27 patients. Since one patient presents with a psychotic disorder, an exploratory study of markers of schizophrenia associated with GABAergic neurotransmission was performed in fgf14 −/− mice, a preclinical model that replicates motor and learning deficits of SCA27. Methods. A comprehensive characterization that included clinical assessments, cognitive tests, structural neuroimaging studies, brain metabolism with 18 F-fluorodeoxyglucose PET ([18F] FDG PET) and genetic analyses was performed. Brains of fgf14 −/− mice were studied with immunohistochemistry. Results. Nine patients had ataxia, and all affected patients harboured an interstitial deletion of chromosome 13q33.1 encompassing the entire FGF14 and integrin subunit beta like 1 ( ITGBL1 ) genes. New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients. Hypometabolism in the PFC was far more pronounced in a SCA27 patient with psychosis. Reduced expression of VGAT was found in the mPFC of fgf14 −/− mice. Conclusions. This is the second largest SCA27 family identified to date. We provide new clinical and preclinical evidence for a significant psychiatric component in SCA27, strengthening the hypothesis of FGF14 as an important modulator of psychiatric disease.