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 suggested an association between 14-3-3 dysregulation and schizophrenia. Methods We characterized behavioral and functional changes in transgenic mic...
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Veröffentlicht in: | Biological psychiatry (1969) 2015-09, Vol.78 (6), p.386-395 |
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Zusammenfassung: | Abstract Background The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies suggested an association between 14-3-3 dysregulation and schizophrenia. Methods We characterized behavioral and functional changes in transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. Results We recently showed that 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. We report here that these 14-3-3 FKO mice display other behavioral deficits that 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. In particular, 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 secondary 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. |
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ISSN: | 0006-3223 1873-2402 |
DOI: | 10.1016/j.biopsych.2015.02.015 |