Neurodevelopmental and neuropsychiatric behaviour defects arise from 14-3-3ζ deficiency

Abstract

Complex neuropsychiatric disorders are believed to arise from multiple synergistic deficiencies within connected biological networks controlling neuronal migration, axonal pathfinding and synapse formation. Here, we show that deletion of 14-3-3ζ causes neurodevelopmental anomalies similar to those seen in neuropsychiatric disorders such as schizophrenia, autism spectrum disorder and bipolar disorder. 14-3-3ζ-deficient mice displayed striking behavioural and cognitive deficiencies including a reduced capacity to learn and remember, hyperactivity and disrupted sensorimotor gating. These deficits are accompanied by subtle developmental abnormalities of the hippocampus that are underpinned by aberrant neuronal migration. Significantly, 14-3-3ζ-deficient mice exhibited abnormal mossy fibre navigation and glutamatergic synapse formation. The molecular basis of these defects involves the schizophrenia risk factor, DISC1, which interacts isoform specifically with 14-3-3ζ. Our data provide the first evidence of a direct role for 14-3-3ζ deficiency in the aetiology of neurodevelopmental disorders and identifies 14-3-3ζ as a central risk factor in the schizophrenia protein interaction network.

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

“…Several studies have shown that the isoform14-3-3ζ has an association with schizophrenia and related neurodevelopmental disorders on the gene- (Jia et al, 2004;Fromer et al, 2014;Toma et al, 2014), gene expression- (Middleton et al, 2005;Wong et al, 2005), and protein level (Sivagnanasundaram et al, Pharmacology, Biochemistry andBehavior 138 (2015) 1-8 2007;English et al, 2009;Focking et al, 2011;Schubert et al, 2015). We found that 14-3-3ζ KO mice display several schizophrenia-like behavioural deficits such as hyperactivity and disrupted sensorimotor gating, impaired novel object recognition, impaired learning in a water crossmaze escape task, and lower levels of anxiety in the elevated plus maze (Cheah et al, 2012). As previously reported, we found that clozapine ameliorated hyperactivity in 14-3-3ζ KO mice (Ramshaw et al, 2013).…”

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

“…Several previous transcriptomic and proteomic analyses have identified alterations in 14-3-3 protein isoforms in postmortem tissue of people with schizophrenia and bipolar disorder (Altar et al, 2009;English et al, 2011), and genetic association with these disorders has been reported (Grover et al, 2009;Jia et al, 2004;Wong et al, 2005). Mice lacking the isoform 14-3-3ζ display significant deficits in hippocampus-dependent functions such as working memory, sensory gating, and associative learning (Cheah et al, 2012;Qiao et al, 2014) and these changes are associated with decreased levels of NMDA receptors in the postsynaptic density (PSD) of CA1 pyramidal neurons, leading to deficits in hippocampal long-term synaptic plasticity (Qiao et al, 2014).…”

Genealogical correspondence of a forebrain centre implies an executive brain in the protostome–deuterostome bilaterian ancestor

“…Dysfunction implicated in Angelman syndrome [49,50] CaMKII: Encodes a calcium/calmodulin-activated protein kinase. CaMKII immunoreactivity is most highly concentrated in the mushroom body lobes and calyces [51] 14-3-3z: Encodes 14-3-3 proteins necessary for neurodevelopment and social cognition [52] leo: Encodes 14-3-3z orthologue Leonardo, enriched in mushroom bodies and necessary for olfactory learning and memory [53] rstb.royalsocietypublishing.org Phil. Trans.…”