AKTing Up in Schizophrenia: Examination of Schizophrenia-related Phenotypes and the Involvement of AKT1 in Dopamine-dependent Behaviors Using Akt1 Knockout Mice
Date Issued
2010
Date
2010
Author(s)
Chen, Yi-Wen
Abstract
Schizophrenia appears to be a multifactorial disorder and accumulating evidence from human genetic and animal studies suggests that AKT1 (protein kinase Bα) might play certain roles in the pathogenesis of this disorder. Compared with human genetic studies, a mutant mouse model is a simple and relatively straightforward approach for determining the causal relationships and biological functions of AKT1 in the pathogenesis of schizophrenia. This master’s thesis aimed to study the roles of AKT1 in schizophrenia-related phenotypes and dopamine-dependent behaviors using AKT1 mutant mice as a model. In study 1, both male and female Akt1-/- mice displayed normal behavioral profiles in a battery of behavioral tasks but female mutant mice showed sex-specific alterations in immobility in the tail suspension test and in acoustic prepulse inhibition (PPI) compared with their wild-type (WT) controls. Female Akt1-/- mice also exhibited neuromorphological abnormalities in the GFP-labeled pyramidal neurons in the auditory cortex compared with those of the controls. Neither raclopride nor clozapine (antipsychotics) alleviated such PPI deficit in Akt1-/- females but it was mitigated by 8-OH-DPAT and SB216763 (indirect/direct Glycogen synthase kinase 3 (GSK3) inhibitors). The findings in study 1 not only reveal a sex-specific PPI deficit and related neuromorphological alterations in female Akt1-/- mice but also highlight the importance of AKT1 in the dopamine-dependent response and a pharmacogenetic effect of AKT1 on treatment selection. In study 2, the roles of AKT1 in the regulation dopamine signaling are further examined through methamphetamine (Meth)-induced behavioral sensitization and dopaminergic compound challenges. Male Akt1-/- mice were evident to be less sensitive to Meth-induced behavioral sensitization than their WT controls, whereas such genotypic reduction of hyperlocomotion did not appear in females mice. Such sex difference was further observed by co-injections of Meth with dopamine D2 receptor (DRD2) agonist/antagonist (i.e., quinpirole and raclopride) in Meth-sensitized mice and by measuring Meth-induced striatal brain activity using microPET with 18F-FDG, especially 60-90 min after Meth injection. Interestingly, the reduction of Meth-induced behavioral sensitization in Male Akt1-/- mice can be rescued by daily injections of 17β-estradiol. These results suggest a region-specific, temporal-specific and DRD2-specific sex difference of AKT1 in the regulation of Meth-related hyperactivity and estrogen might play some roles in this process. Taken all together, these findings support the involvement of AKT1 in the actions of dopamine and further indicate a sexually dimorphic effect of AKT1 in the regulation of behavioral phenotypes and DA-dependent responses, which might be affected by estrogen.
Subjects
Akt1 mutant mice
sex difference
prepulse inhibition
antipsychotics
GSK-3 inhibitor
neuromorphology
methamphetamine
PET scan
Type
thesis
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