Behavioral analyses of a forebrain glutamatergic neuron specific Ywhae conditional knockout mouse model

The seven mammalian isoforms of 14-3-3 are each encoded by a unique gene and function as phosphorylation dependent protein modulators. Because 14-3-3 proteins have particularly high expression in the brain, they have been implicated in a variety of neuronal functions. Recently, we showed that functional knockout of all 14-3-3 isoforms in forebrain glutamatergic neurons of mice is sufficient to induce schizophrenia-like endophenotypes. Human and animal studies have linked mutations in Ywhae and 14-3-3ε expression changes to certain neurodevelopmental and psychiatric diseases. In this study, we conditionally knocked out 14-3-3ε from forebrain glutamatergic neurons by crossing Ywhaeflox/flox mice with CaMKIIα-Cre mice. Ywhaeflox/flox Cre+ (conditional knockout -CKO) mice and their Ywhaeflox/flox Cre- (double-flox control - dFlC) littermates were put through a battery of behavioral tests to assess their behavioral endophenotypes. Ywhae CKO mice exhibited significant differences from dFlC mice in some of the behaviors examined. We also found several significant sex differences within our model. Furthermore, we compared two viral 14-3-3 knockout methods and found that CaMKIIα promoter driven difopein expression in wildtype mice is more efficient than Cre/loxP driven difopein expression in CaMKIIα-Cre mice. Collectively our results indicate that knocking out 14-3-3ε in glutamatergic forebrain neurons via this strategy is not sufficient to induce schizophrenia-like behavioral alterations. In the future, using different mouse line or knockout scheme may help further elucidate the isoform specific role of 14-3-3ε in the forebrain.

• Publication year

  2025

• Venue

  PLoS ONE

• Publication date

  2025-11-11

• Fields of study

  Biology, Medicine, Psychology

• Identifiers
  DOI 10.1371/journal.pone.0335427PMID 41218078PMCID 12604760
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Systematic optimization and prediction of cre recombinase for precise genome editing in mice

  2025cited by this paper
• Inhibition of 14‐3‐3 proteins increases the intrinsic excitability of mouse hippocampal CA1 pyramidal neurons

  2024cited by this paper
• Large-Scale Genome-Wide Optimization and Prediction of the Cre Recombinase System for Precise Genome Manipulation in Mice

  2024cited by this paper
• YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse.

  2023cited by this paper
• USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder

  2023cited by this paper
• Glutamatergic dysfunction in Schizophrenia

  2022cited by this paper
• 14-3-3 Dysfunction in Dorsal Hippocampus CA1 (dCA1) Induces Psychomotor Behavior via a dCA1-Lateral Septum-Ventral Tegmental Area Pathway

  2022cited by this paper
• Aberrant glial activation and synaptic defects in CaMKIIα-iCre and nestin-Cre transgenic mouse models

  2022cited by this paper
• The 14-3-3 Protein Family and Schizophrenia

  2022cited by this paper
• A Selective Review of the Excitatory-Inhibitory Imbalance in Schizophrenia: Underlying Biology, Genetics, Microcircuits, and Symptoms

  2021cited by this paper
• Substrains matter in phenotyping of C57BL/6 mice

  2021cited by this paper
• 14-3-3 proteins promote synaptic localization of N-methyl d-aspartate receptors (NMDARs) in mouse hippocampal and cortical neurons

  2021cited by this paper
• Inhibition of 14-3-3 Proteins Alters Neural Oscillations in Mice

  2021cited by this paper
• Dysregulation of peripheral expression of the YWHA genes during conversion to psychosis

  2020cited by this paper
• Identification of Key Regulatory Genes and Pathways in Prefrontal Cortex of Alzheimer’s Disease

  2020cited by this paper
• Sex bias and omission in neuroscience research is influenced by research model and journal, but not reported NIH funding.

  2020cited by this paper
• An atlas of the protein-coding genes in the human, pig, and mouse brain

  2020cited by this paper
• Meta-Analysis of Sensorimotor Gating Deficits in Patients With Schizophrenia Evaluated by Prepulse Inhibition Test.

  2020cited by this paper
• Behavioral Tasks Evaluating Schizophrenia-like Symptoms in Animal Models: A Recent Update

  2020cited by this paper
• Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses

  2020cited by this paper
• Region-specific inhibition of 14-3-3 proteins induces psychomotor behaviors in mice

  2019cited by this paper
• Contrasting characteristic behaviours among common laboratory mouse strains

  2019cited by this paper
• Long-Lasting Rescue of Network and Cognitive Dysfunction in a Genetic Schizophrenia Model.

  2019cited by this paper
• Hippocampal subregion abnormalities in schizophrenia: A systematic review of structural and physiological imaging studies

  2018cited by this paper
• 14-3-3 Proteins in Glutamatergic Synapses

  2018cited by this paper
• Neurodevelopmental Genetic Diseases Associated With Microdeletions and Microduplications of Chromosome 17p13.3

  2018cited by this paper
• Exploratory rearing: a context- and stress-sensitive behavior recorded in the open-field test

  2018cited by this paper
• The YWHAE gene confers risk to major depressive disorder in the male group of Chinese Han population

  2017cited by this paper
• Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age

  2016cited by this paper
• Dysregulated 14-3-3 Family in Peripheral Blood Leukocytes of Patients with Schizophrenia

  2016cited by this paper
• Why sex differences in schizophrenia?

  2016cited by this paper
• omplete ablation of the 14-3-3 epsilon protein results in multiple efects in neuropsychiatric behaviors

  2016cited by this paper
• Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice.

  2015cited by this paper
• Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability.

  2015cited by this paper
• Epistatic and gene wide effects in YWHA and aromatic amino hydroxylase genes across ADHD and other common neuropsychiatric disorders: Association with YWHAE

  2015cited by this paper
• Identification of Novel 14-3-3 Residues That Are Critical for Isoform-specific Interaction with GluN2C to Regulate N-Methyl-d-aspartate (NMDA) Receptor Trafficking*

  2015cited by this paper
• Contextual and Cued Fear Conditioning Test Using a Video Analyzing System in Mice

  2014cited by this paper
• 14-3-3ε and ζ Regulate Neurogenesis and Differentiation of Neuronal Progenitor Cells in the Developing Brain

  2014cited by this paper
• The polymorphism of YWHAE, a gene encoding 14-3-3epsilon, and orbitofrontal sulcogyral pattern in patients with schizophrenia and healthy subjects.

  2014cited by this paper
• The Polymorphism of YWHAE, a Gene Encoding 14-3-3Epsilon, and Brain Morphology in Schizophrenia: A Voxel-Based Morphometric Study

  2014cited by this paper
• 14-3-3 Proteins Are Required for Hippocampal Long-Term Potentiation and Associative Learning and Memory

  2014cited by this paper
• Association of YWHAE gene polymorphism with suicidal behavior

  2013cited by this paper
• Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis.

  2013cited by this paper
• Pharmacological disruption of mouse social approach behavior: relevance to negative symptoms of schizophrenia.

  2013cited by this paper
• Polymorphisms and haplotypes in the YWHAE gene increase susceptibility to bipolar disorder in Chinese Han population.

  2012cited by this paper
• Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia

  2012cited by this paper
• Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin A liver injury.

  2011cited by this paper
• Assessment of Social Interaction Behaviors

  2011cited by this paper
• Impairment of the tyrosine hydroxylase neuronal network in the orbitofrontal cortex of a genetically modified mouse model of schizophrenia.

  2011cited by this paper
• Immunohistochemical study of vesicle monoamine transporter 2 in the hippocampal region of genetic animal model of schizophrenia

  2010cited by this paper
• Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes

  2010cited by this paper
• Growth factor-dependent trafficking of cerebellar NMDA receptors via protein kinase B/Akt phosphorylation of NR2C.

  2009cited by this paper
• Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia.

  2008cited by this paper
• Structural basis for protein–protein interactions in the 14-3-3 protein family

  2006cited by this paper
• A mouse model system for genetic analysis of sociability: C57BL/6J versus BALB/cJ inbred mouse strains.

  2006cited by this paper
• Genetic isolation of transport signals directing cell surface expression

  2005cited by this paper
• Behavioral differences among fourteen inbred mouse strains commonly used as disease models.

  2005cited by this paper
• The neuroscience of mammalian associative learning.

  2005cited by this paper
• Mammalian and yeast 14-3-3 isoforms form distinct patterns of dimers in vivo.

  2003cited by this paper
• The 14-3-3 Proteins: Gene, Gene Expression, and Function

  2003cited by this paper
• 14-3-3 proteins in the nervous system

  2003cited by this paper
• 14-3-3ε is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller–Dieker syndrome

  2003cited by this paper
• 14‐3‐3 proteins: key regulators of cell division, signalling and apoptosis

  2001cited by this paper
• A dynamically regulated 14-3-3, Slob, and Slowpoke potassium channel complex in Drosophila presynaptic nerve terminals.

  1999cited by this paper
• Developmental expression of the CaM kinase II isoforms: ubiquitous gamma- and delta-CaM kinase II are the early isoforms and most abundant in the developing nervous system.

  1999cited by this paper
• Developmental expression of the CaM kinase II isoforms: ubiquitous γ- and δ-CaM kinase II are the early isoforms and most abundant in the developing nervous system

  1999cited by this paper
• A new continuous alternation task in T-maze detects hippocampal dysfunction in mice. A strain comparison and lesion study.

  1998cited by this paper
• Mutations in the Hydrophobic Surface of an Amphipathic Groove of 14-3-3ζ Disrupt Its Interaction with Raf-1 Kinase*

  1998cited by this paper
• The structural basis for 14-3-3:phosphopeptide binding specificity.

  1997cited by this paper
• Subregion- and cell type-restricted gene knockout in mouse brain.

  1996cited by this paper
• Crystal structure of the zeta isoform of the 14-3-3 protein

  1995cited by this paper
• In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain

  1990cited by this paper
• Molecular dissection of a contiguous gene syndrome: frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated "island" in the Miller-Dieker chromosome region.

  1989cited by this paper
• Molecular cloning of cDNA coding for brain-specific 14-3-3 protein, a protein kinase-dependent activator of tyrosine and tryptophan hydroxylases.

  1988cited by this paper
• Changes in the subcellular distribution of calmodulin-kinase II during brain development.

  1985cited by this paper
• Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain

  1985cited by this paper
• Human 14‐3‐3 Protein: Radioimmunoassay, Tissue Distribution, and Cerebrospinal Fluid Levels in Patients with Neurological Disorders

  1982cited by this paper
• Subcellular localization of the 52,000 molecular weight major postsynaptic density protein.

  1982cited by this paper
• Please Scroll down for Article Journal of Neurogenetics Behavioral Differences among C57bl/6 Substrains: Implications for Transgenic and Knockout Studies Behavioral Differences among C57bl/6 Substrains: Implications for Transgenic and Knockout Studies

  year unknowncited by this paper

• No citing papers are available for this paper.