# Behavioral analyses of a forebrain glutamatergic neuron specific Ywhae conditional knockout mouse model

## TL;DR

This study investigates the effects of knocking out a specific brain protein in mice to understand its role in psychiatric disorders.

## Contribution

The study introduces a new mouse model with conditional knockout of 14-3-3ε in forebrain glutamatergic neurons and evaluates its behavioral effects.

## Key findings

- Conditional knockout of 14-3-3ε in forebrain glutamatergic neurons did not induce schizophrenia-like behaviors in mice.
- Significant sex differences were observed in the behavioral endophenotypes of the mouse model.
- A viral knockout method using the CaMKIIα promoter was found to be more efficient than the Cre/loxP method in this model.

## Abstract

The seven mammalian isoforms of 14-3-3 are each encoded by a unique gene and function as phosphorylation dependent protein modulators. Because 14-3-3 proteins have particularly high expression in the brain, they have been implicated in a variety of neuronal functions. Recently, we showed that functional knockout of all 14-3-3 isoforms in forebrain glutamatergic neurons of mice is sufficient to induce schizophrenia-like endophenotypes. Human and animal studies have linked mutations in Ywhae and 14-3-3ε expression changes to certain neurodevelopmental and psychiatric diseases. In this study, we conditionally knocked out 14-3-3ε from forebrain glutamatergic neurons by crossing Ywhaeflox/flox mice with CaMKIIα-Cre mice. Ywhaeflox/flox
Cre+ (conditional knockout -CKO) mice and their Ywhaeflox/flox
Cre- (double-flox control - dFlC) littermates were put through a battery of behavioral tests to assess their behavioral endophenotypes. Ywhae CKO mice exhibited significant differences from dFlC mice in some of the behaviors examined. We also found several significant sex differences within our model. Furthermore, we compared two viral 14-3-3 knockout methods and found that CaMKIIα promoter driven difopein expression in wildtype mice is more efficient than Cre/loxP driven difopein expression in CaMKIIα-Cre mice. Collectively our results indicate that knocking out 14-3-3ε in glutamatergic forebrain neurons via this strategy is not sufficient to induce schizophrenia-like behavioral alterations. In the future, using different mouse line or knockout scheme may help further elucidate the isoform specific role of 14-3-3ε in the forebrain.