511 Eliminating System xc- Signaling Between Astrocytes and Neurons Selectively Impairs Complex Cognition

• Published in: Journal of clinical and translational science Vol. 7; no. s1; p. 145
• Main Authors: Simandl, Gregory, Simandl, Gregory J., Hess, Evan, Kong, Linghai, Raddatz, Nicholas J., Hurley, Matthew M., Maunze, Brian, Choi, SuJean, Geurts, Aaron M., Baker, David A.
• Format: Journal Article
• Language: English
• Published: Cambridge Cambridge University Press 01.04.2023
• Subjects: Astrocytes; Behavior; Body temperature; Body weight; Cocaine; Cognition; Drug delivery; Drug development; Embryos; Growth rate; Impulsive behavior; Locomotor activity; Metabolism; Nuclease; Operant conditioning; Other; Pattern recognition; Population studies; Reaction time task; Zinc finger proteins
• DOI: 10.1017/cts.2023.510
• ISSN: 2059-8661

OBJECTIVES/GOALS: We aim to discover safer and more effective therapeutics for CNS disorders. Current therapeutic development is hindered by dosing out drugs for safe consumption. By identifying proteins with narrow functional roles in the brain (i.e., behavioral control), we can develop drugs targeting these proteins for improved treatment safety and efficacy. METHODS/STUDY POPULATION: We focused on an evolutionarily new, non-neuronal, non-synaptic glutamate signaling mechanism, system xc- (Sxc). Sxc activity was eliminated by mutating the gene Slc7a11 through pronuclear injection of zinc-finger nucleases into Sprague Dawley rat embryos to create a line of rats lacking Sxc (MSxc). To confirm Sxc mutation, we verified that tissue from MSxc rats had a complete lack of xCT, which is the regulatory subunit of Sxc that is encoded by Slc7a11. We also verified that astrocyte cultures generated from MSxc tissue lacked cystine-evoked glutamate release. Next, we measured development (body weight), CNS regulation of metabolism, and other indicators of generalized, non-specific brain function as well as behaviors that are reliant on behavioral control, such as impulse control and response inhibition. RESULTS/ANTICIPATED RESULTS: Eliminating Sxc was not lethal and did not impair development or produce widespread changes in brain function as is commonly observed when deleting other glutamate mechanisms. MSxc rats did not differ from wildtype in growth rate, central regulation of metabolism as reflected by absolute or diurnal changes in core body temperature, locomotor activity in a familiar or novel environment, or simple forms of cognition such as novel object recognition, or operant responding (food and cocaine-reinforced). In contrast, behaviors that rely on behavioral control were impaired. MSxc rats displayed deficits in impulse control and behavioral flexibility. We hypothesize that MSxc rats will also show deficits in response inhibition using the stop signal reaction time task, a common metric used in clinical populations. DISCUSSION/SIGNIFICANCE: Eliminating Sxc activity in rats produced deficits in behaviors reliant on impulse control, without impacting development or simple brain function. These results show the potential of targeting Sxc to restore behavioral control without generating therapeutically limiting adverse effects resulting from non-specific changes in brain function.