Increasing Ambient GABA Levels in the Hippocampus to Improve Cognition in a Mouse Model of Schizophrenia: A Research Protocol

Abstract

Introduction: Schizophrenia is a complex psychiatric disorder characterized by cognitive, positive, and negative symptoms, with cognitive impairments significantly affecting learning, memory, and executive functions. The hippocampus, particularly the CA1 region, is a critical area of interest due to its role in learning and memory and its dysfunction in schizophrenia. This protocol explores the effects of increasing ambient Gamma-Aminobutyric Acid (GABA) levels in the CA1 region on cognitive functions in a Methylazoxymethanol Acetate (MAM) model of schizophrenia. Methods: Utilizing a two-by-two factorial design, male Sprague-Dawley rats undergo either a sham or MAM treatment, followed by a control or GABA modulation intervention. The study will employ GABA transporter inhibitor Tiagabine to increase ambient GABA levels and assess its impact on neuronal excitability and cognitive function. Behavioural assessments will include the Morris water maze and the Attentional set-shifting test to evaluate spatial memory and cognitive flexibility. Histological examinations and electrophysiological measurements will provide insights into structural and functional changes in the hippocampus. Results: The results are expected to demonstrate neurodevelopmental disruptions in MAM-treated offspring and improvements in cognitive performance following GABA modulation. Enhanced spatial memory and cognitive flexibility are anticipated in MAM-treated rats with GABA modulation, as evidenced by performance in the Morris water maze and Attentional set-shifting test. Electrophysiological recordings are likely to show increased tonic inhibition in the CA1 region. Discussion: This study aims to extend the understanding of tonic inhibition in schizophrenia treatment. By focusing on ambient GABA modulation, the research could offer novel insights into therapeutic strategies for schizophrenia, especially in enhancing cognitive functions. However, the translational applicability of intracerebral administration of uptake inhibitors like Tiagabine poses a significant challenge, highlighting the need for future research in more clinically viable methods of GABA modulation. Conclusion: This study was designed to contribute to schizophrenia research, particularly in understanding cognitive impairments and developing potential therapeutic strategies targeting the GABAergic system. The proposed findings could pave the way for novel treatments, improving the quality of life for individuals with schizophrenia.