Regional Inhibition of 14-3-3 Proteins Induces Schizophrenia-Related Behaviors via Disturbed Neuronal Circuits

Genetic animal models have become an increasingly useful tool in addressing pathophysiological changes in neuropsychiatric disorders at the molecular, synaptic and circuitry levels. Previous genetic and postmortem studies have identified several 14-3-3 isoforms as potential candidate risk genes for schizophrenia. 14-3-3 proteins are a family of homologous proteins involved in many biological processes including signaling, neurite outgrowth and ion channel regulation. In order to investigate the potential associate between 14-3-3 dysregulation and schizophrenia, our lab has created a novel mouse model that addresses the collective function of all 14-3-3 isoforms in the brain. These transgenic mice express a 14-3-3 peptide inhibitor (YFP-difopein) that antagonizes 14-3-3 binding to its endogenous partners and is thus considered a 14-3-3 functional knockout (FKO). We have shown that these 14-3-3 FKO mice exhibit a variety of behavioral and morphological deficits reminiscent of the core endophenotypes of established schizophrenia animal models. This dissertation aims to dissect the molecular pathways and region-specific circuit connections that may be responsible for induction of particular schizophrenic endophenotypes. In Chapter 2, we found that when 14-3-3 proteins are inhibited in the 14-3-3 FKO mice this causes dysregulation of NMDA receptors and actin-signaling at the synapse, possibly leading to deficits in synaptic activity and spine formation. In Chapter 3, we created adeno-associated viruses (AAVs) to determine the brain regions responsible for the circuit control of particular schizophrenic-associated behaviors. We determined that disruption of 14-3-3 function within the dorsal hippocampus alone or the hippocampus and prefrontal cortex together is sufficient to induce schizophrenia-associated behavioral endophenotypes. This effect is most likely due to disturbance in circuit connections within the prefrontal cortex and hippocampus, as restoring 14-3-3 function in both brain regions was necessary in order to attenuate psychomotor disturbances in the 14-3-3 FKO mice. Together, the work presented in this dissertation sheds some light on the role that 14-3-3 plays in the development of psychiatric disorders and provides a framework for future research of schizophrenic models.