Dataset Information

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.

SUBMITTER: Alshammari TK

PROVIDER: S-EPMC5070049 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Alshammari T K TK Alshammari M A MA Nenov M N MN Hoxha E E Cambiaghi M M Marcinno A A James T F TF Singh P P Labate D D Li J J Meltzer H Y HY Sacchetti B B Tempia F F Laezza F F

Translational psychiatry 20160510

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, ...[more]

PMID: 27163207

Similar Datasets

Project description:ImportanceIt is not clear how common pure vascular cognitive impairment (VCI) is in the absence of Alzheimer disease (AD) and/or other neurodegenerative pathologies.ObjectiveTo identify participants without AD and other neurodegenerative pathologies and determine the extent to which cerebrovascular disease pathologies were associated with cognitive impairment.Design, setting, and participantsThis clinical pathological study included participants from 2 ongoing community-based cohorts that began enrollment in 1994 and 1997. Prior to death, participants were observed for a mean (SD) of 8.4 (5.3) years with annual assessments. From 2096 participants who died, 1799 (85.8%) underwent autopsy and 1767 had complete postmortem pathological examination data at the time of data analyses. To identify participants without neurodegenerative pathologies, we categorized them in 3 subgroups. A vascular subgroup was composed of participants without significant levels of neurodegenerative brain pathologies. A neurodegenerative subgroup was composed of participants without significant levels of cerebrovascular disease pathologies. A mixed subgroup was composed of the rest of the participants. Data were analyzed from May 2021 to July 2022.ExposuresBrain pathology indices obtained by postmortem pathological assessments.Main outcomes and measuresThe primary outcome was cognitive impairment defined by presence of mild cognitive impairment or dementia. The secondary outcome was cognition assessed by 19 neuropsychological tests.ResultsOf 1767 included participants, 1189 (67.3%) were women, and the mean (SD) age at death was 89.4 (6.6) years. In the vascular subgroup (n = 369), cognitive impairment was present in 156 participants (42.3%) and was associated with cerebrovascular disease pathologies (macroinfarcts: odds ratio [OR], 2.05; 95% CI, 1.49-2.82; P < .001; arteriolosclerosis in basal ganglia: OR, 1.35; 95% CI, 1.04-1.76; P = .03) but not AD or other neurodegenerative pathologies, an indication of pure VCI. In mixed-effects models including all the pathologies, only macroinfarcts were associated with a faster cognitive decline rate (estimate, -0.019; SE, 0.005; P < .001) in the vascular subgroup. Further analyses identified macroinfarcts in the frontal white matter to be associated with faster cognitive decline rate when macroinfarcts of cortical and subcortical brain regions were examined in a single model.Conclusions and relevanceIn this study, pure VCI was not rare. Macroinfarcts, specifically in frontal white matter, were the main cerebrovascular disease pathologies associated with cognitive decline in pure VCI.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets