| The 14-3-3 family of proteins is implicated in the regulation of a broad range of key neuronal processes. Previous human and animal studies have provided evidence for an association between 14-3-3 proteins and schizophrenia. Here, I report the characterization of the 14-3-3 functional knockout (FKO) mice that perinatally express an isoform-independent 14-3-3 inhibitor peptide in the brain. Fluorescent microscopy was first used to determine the specific transgene expression pattern in the brain for each 14-3-3 FKO founder line. Results from initial behavioral screenings of the 14-3-3 FKO founder lines identified a variety of behavioral changes in different lines and these alterations are also correlated with specific transgene expression patterns. Further behavior characterization revealed that certain 14-3-3 FKO mice exhibit a variety of behavioral changes that correspond to the core symptoms of schizophrenia. I show that these behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. In addition, administration of dopamine receptor antagonist drugs, such as clozapine or haloperidol, are sufficient to attenuate certain schizophrenia-associated behavioral deficits of the 14-3-3 FKO mice. Disruption of 14-3-3 proteins has previously been linked to improper neuronal development. Consistently, we identify global and region-specific reductions in brain volume and corresponding wet weights. Particularly, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie an altered synaptic activity in the 14-3-3 FKO mice. Together, my data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits. |
