Abstract
The 14-3-3 family of proteins is genetically linked to several psychiatric disorders, including schizophrenia. Our 14-3-3 functional knockout (FKO) mice, as well as other 14-3-3 knockout models, have been shown to exhibit behavioral endophenotypes related to schizophrenia. While specific forebrain regions, such as the prefrontal cortex (PFC) and hippocampus (HP), have been implicated in schizophrenic pathophysiology, the role of these brain regions in the top-down control of specific schizophrenia-associated behaviors has not been examined. Here, we used an adeno-associated virus (AAV) delivered shRNA to knock down the expression of the 14-3-3-inhibitor transgene, thus selectively restoring the function of 14-3-3 in the forebrain of the 14-3-3 FKO mice, we found that injection of the AAV-shRNA into both the PFC and the HP is necessary to attenuate psychomotor activity of the 14-3-3 FKO mice. Furthermore, we found that acute inhibition of 14-3-3, through the delivery of an AAV expressing the 14-3-3 inhibitor to both the PFC and HP, can trigger psychomotor agitation. Interestingly, when assessing the two brain regions separately, we determined that AAV-mediated expression of the 14-3-3 inhibitor specifically within the HP alone is sufficient to induce several behavioral deficits including hyperactivity, impaired associative learning and memory, and reduced sensorimotor gating. In addition, we show that post-synaptic NMDA receptor levels are regulated by acute 14-3-3 manipulations. Taken together, findings from this study directly link 14-3-3 inhibition in specific forebrain regions to certain schizophrenia-associated endophenotypes.
Highlights
Schizophrenia is a debilitating psychiatric disorder characterized by a variety of symptoms encompassing multiple cognitivebehavioral domains, most of which can be attributed to deficits in higher-order brain functions
Since the transgenically expressed [-3] inhibitor difopein is fused with yellow fluorescent protein (YFP), we reasoned that an shRNA against YFP would be effective in knocking down expression of the entire YFP-difopein fusion protein, restoring [-3] functions in the [-3] functional knockout (FKO) mice
We found that schizophrenia-associated behavioral deficits in [-3] FKO mice correlate with high-level transgene expression in the forebrain region, in the cortex and the HP.[15]
Summary
Schizophrenia is a debilitating psychiatric disorder characterized by a variety of symptoms encompassing multiple cognitivebehavioral domains, most of which can be attributed to deficits in higher-order brain functions. As human genetic studies identified a number of risk genes associated with schizophrenia, genetic animal models have become an increasingly valuable tool in addressing pathophysiological changes in schizophrenia at the molecular, synaptic, and circuitry levels.[11,12] Previously, we and others have generated several animal models that target one of these candidate risk genes encoding [-3], which refers to a family of ubiquitous proteins abundantly expressed in the brain.[13,14,15] The [-3] proteins are highly conserved from yeast to humans and consist of seven distinct isoforms (β,γ,ε,η,ζ,σ, and τ) in mammals.[16,17] Single nucleotide polymorphisms (SNPs) of several [-3] isoforms were revealed in various schizophrenic populations by linkage analyses.[18,19,20,21] Ywhah, encoding the 14-3-3η isoform, is located within the established 22q12–13 candidate risk chromosomal region.[22] Decreased expression of [-3] at both the protein and mRNA levels was detected in the brains of schizophrenic patients.[23,24,25] More recently, Ywhag and Ywhaz, encoding 14-3-3γ and ζ isoforms, were identified as members of a group of glutamatergic postsynaptic proteins that are prone to de novo mutations in schizophrenic populations.[26,27,28] Our previous [-3] mouse model is considered to be a functional knockout (FKO).
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