Modeling schizophrenia endophenotypes in drosophila melanogaster: effects of ketamine on anxiety, aggression, locomotion and inflammatory responses

Abstract

Schizophrenia presents a significant challenge in mental health, characterized by a profound distortion of reality, often accompanied by hallucinations, delusions, cognitive deficits and neuroinflammatory processes. Ketamine has been widely used as a pharmacological agent to model schizophrenia symptoms in both human and animal studies. However, the potential of ketamine to induce schizophrenia-like phenotypes in Drosophila melanogaster remains under-investigated. This study therefore investigated the effects of ketamine on anxiety, aggression, locomotor activities, and inflammatory response in Drosophila melanogaster in a bid to develop a pharmacological model of schizophrenia in Drosophila.Virgin male and female Oregon-R flies were collected after eclosion and exposed to four different concentrations of ketamine (100, 250, 500, 1000 µg/mL) for 1 week under standard laboratory conditions (22-25°C, 50-60% humidity). Experimental groups consisted of 10 vials each containing 10 flies each. Anxiety, aggression and locomotory functions were assessed behaviorally through the open field, aggression, and rapid iterative negative geotaxis (RING) assays. Pro-inflammatory and astrogliotic responses were measured immunohistochemically using Tumor necrosis factor-alpha (TNF-α) and Glial fibrillary acidic protein (GFAP) antibodies. General neuronal architecture was evaluated using the H&E histological staining techniques.The results showed a dose-dependent induction of aggressive behavior. Motor function assays demonstrated that ketamine impaired these functions in a dose-dependent manner. Survival assays indicated that higher doses of ketamine reduced survival rates. Immunohistochemical analysis revealed a dose-dependent increase in TNF-α and GFAP mean fluorescence intensity across the treatment groups, indicating upregulation of TNF-α and GFAP expressions. This suggests a robust pro-inflammatory and astrogliotic response to ketamine administration, aligning with the emerging neuroinflammatory endophenotype theory of schizophrenia aetiology and its experimental modeling. Histological analysis displayed significant dose-dependent histopathological changes, including increased cell loss and vacuolization at higher ketamine concentrations.In conclusion the findings suggest that ketamine has potential as a pharmacological model of schizophrenia in Drosophila. Overall, these results contribute to understanding of how ketamine influence key behavioral and neurobiological parameters, offering insights into their potential roles in inducing schizophrenia-like phenotypes like altered behavior and histopathology. Keywords: Ketamine, Drosophila melanogaster, Neuroinflammation, TNF-α, Schizophrenia, GFAP. Received on, 22 January 2025 Accepted on, 06 April 2025 Published on, 12 May 2025