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Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice
Molly Foote1, Haifa Qiao1, Kourtney Graham1
1Department of Biomedical Sciences, Florida State University, College of Medicine, Tallahassee, Florida.
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.
Insights
14-3-3 protein dysfunction in mice leads to behavioral deficits mimicking schizophrenia symptoms. This involves synaptic changes in the brain, offering new insights into the disorder.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- The 14-3-3 protein family regulates critical neuronal functions.
- Previous research links 14-3-3 dysregulation to schizophrenia in humans and animals.
Purpose of the Study:
- To investigate behavioral and functional changes in mice with inhibited 14-3-3 protein activity.
- To explore the link between 14-3-3 dysfunction and schizophrenia-like behaviors.
Main Methods:
- Utilized transgenic mice expressing an isoform-independent 14-3-3 inhibitor peptide in the brain.
- Characterized behavioral and functional alterations in these genetically modified mice.
Main Results:
- 14-3-3 functional knockout (FKO) mice exhibited impairments in associative learning and memory.
- These mice displayed behavioral deficits mirroring core schizophrenia symptoms.
- Reduced dendritic complexity and spine density in forebrain excitatory neurons were observed, linked to altered synaptic connectivity.
- Molecular analysis revealed dysregulated actin dynamics due to disrupted 14-3-3 regulation of phosphorylated cofilin.
Conclusions:
- Established a connection between 14-3-3 protein dysfunction and schizophrenia-associated behavioral deficits.
- Highlighted the role of synaptic alterations, specifically dendritic spine defects, in these deficits.
- Provided molecular insights into the mechanisms underlying these changes, involving actin dynamics.
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