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

Biol Psychiatry. 2015 Sep 15;78(6):386-95. doi: 10.1016/j.biopsych.2015.02.015. Epub 2015 Feb 19.

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.

Keywords: 14-3-3 Proteins; Dendritic spines; Neurotransmission; Prefrontal cortex; Schizophrenia; Transgenic mouse model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / antagonists & inhibitors
  • 14-3-3 Proteins / genetics
  • 14-3-3 Proteins / metabolism*
  • Animals
  • Antipsychotic Agents / administration & dosage
  • Behavior, Animal / drug effects
  • Catenins / metabolism
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Clozapine / administration & dosage
  • Cofilin 1 / metabolism
  • Delta Catenin
  • Dendrites / metabolism
  • Dendrites / pathology
  • Disease Models, Animal
  • Dopamine / metabolism
  • Haloperidol / administration & dosage
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Prepulse Inhibition / drug effects
  • Proteins / genetics
  • Receptors, Dopamine / metabolism
  • Schizophrenia / genetics
  • Schizophrenia / metabolism*
  • Schizophrenia / physiopathology*
  • Schizophrenic Psychology*
  • Synaptic Transmission*

Substances

  • 14-3-3 Proteins
  • Antipsychotic Agents
  • Catenins
  • Cofilin 1
  • Proteins
  • Receptors, Dopamine
  • difopein
  • Clozapine
  • Haloperidol
  • Dopamine
  • Delta Catenin