ABSTRACT
AKT1 controls important processes in medial temporal lobe (MTL) development and plasticity, but the impact of human genetic variation in AKT1 on these processes is not known in healthy or disease states. Here, we report that an AKT1 variant (rs1130233) previously associated with AKT1 protein expression, prefrontal function and schizophrenia, affects human MTL structure and memory function. Further, supporting AKT1's role in transducing hippocampal neuroplasticity and dopaminergic processes, we found epistasis with functional polymorphisms in BDNF and COMT--genes also implicated in MTL biology related to AKT1. Consistent with prior predictions that these biologic processes relate to schizophrenia, we found epistasis between the same AKT1, BDNF and COMT functional variants on schizophrenia risk, and pharmacogenetic interactions of AKT1 with the effects on cognition and brain volume measures by AKT1 activators in common clinical use--lithium and sodium valproate. Our findings suggest that AKT1 affects risk for schizophrenia and accompanying cognitive deficits, at least in part through specific genetic interactions related to brain neuroplasticity and development, and that these AKT1 effects may be pharmacologically modulated in patients.
Subject(s)
Polymorphism, Single Nucleotide/genetics , Proto-Oncogene Proteins c-akt/genetics , Schizophrenia/genetics , Schizophrenia/pathology , Temporal Lobe/pathology , Antipsychotic Agents/therapeutic use , Brain Mapping , Brain-Derived Neurotrophic Factor/genetics , Catechol O-Methyltransferase/genetics , Cognition Disorders/drug therapy , Cognition Disorders/etiology , Economics, Pharmaceutical , Epistasis, Genetic/drug effects , Epistasis, Genetic/genetics , Female , Genetic Association Studies , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Memory Disorders/drug therapy , Memory Disorders/etiology , Memory Disorders/genetics , Neuropsychological Tests , Oxygen/blood , Photic Stimulation , Reaction Time/drug effects , Reaction Time/genetics , Schizophrenia/complications , Schizophrenia/drug therapy , Temporal Lobe/blood supply , Temporal Lobe/drug effectsABSTRACT
1,1-Bis(4-ethoxyphenyl)-2-nitropropane (GH74) was evaluated as an oviposition deterrent for the sheep blowfly Lucilia cuprina. In several test situations, flies laid only very few egg masses on fleece to which 0.5% GH74 had been applied, and which had been exposed in the field for up to 6 months. However, a significant number of egg masses were laid on the breech of severely scouring sheep when tested several weeks after application of GH74 at the same concentration. Procedures for evaluating oviposition deterrents against sheep blowfly are discussed.
