Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice

Abstract

Background The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies have suggested an association between 14-3-3 dysregulation and schizophrenia. Methods We characterized the behavioral and functional changes in the transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. Results We have recently shown that the 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. Here, we report that these 14-3-3 FKO mice display other behavioral deficits which correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. Particularly, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics due to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin. Conclusions Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits.

In-vivo administration of clozapine affects behaviour but does not reverse dendritic spine deficits in the 14-3-3ζ KO mouse model of schizophrenia-like disorders

“…Previous studies in 14-3-3ζ -depleted mice have reported a beneficial effect of clozapine on isolated behavioural paradigms such as hyperactivity (Ramshaw et al, 2013;Foote et al, 2015) and prepulse inhibition (Foote et al, 2015). The incorporation of a more comprehensive test battery in our study shows that clozapine effects are not clear-cut in this model.…”

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

“…The 14-3-3 protein family is highly associated with neurotransmitting processes [28], with some isoforms particularly enriched in synapses, and the YWHAZ and YWHAE genes were previously associated with schizophrenia [33][34][35]. For instance, broad 14-3-3 functional knockout mice, in addition to showing schizophrenia-like behavior, have high dopamine levels and a decrease in dendritic complexity and spine density, defects linked to schizophrenia [36]. As the main white matter region in the brain, the CC is composed mostly of glia cells and neuronal axons.…”

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

“…Inhibition of 14‐3‐3s promotes cell loss in several PD models, while overexpression of 14‐3‐3s, in particular 14‐3‐3 θ , reduces toxicity in several PD models 5, 15, 16, 17. 14‐3‐3s also impact neurite growth, spine density, and cognitive function: a functional 14‐3‐3 knockout demonstrates reduced dendritic length and spine numbers, reduced impaired long‐term potentiation, and abnormalities in contextual fear conditioning 5, 41, 42. The loss of soluble 14‐3‐3s observed here may contribute to synapse loss and cognitive decline.…”