Authors :
Presenting Author: Yana Van Den Herrewegen, PhD – UCB Biopharma SRL
Jerome Clasadonte, PhD – UCB Biopharma SRL; Natalia Rodriguez, PhD – UCB Biopharma SRL; Eleonora Lugara, PhD – UCB Biopharma SRL; Emmanuel Goursaud, MSc – UCB Biopharma SRL; Eric Gillent, MSc – UCB Biopharma SRL; Pierre Bonnaillie, MSc – UCB Biopharma SRL; Georges Mairet-Coello, PhD – UCB Biopharma SRL; Marcella Widya, MSc – UCB Biopharma SRL; Catherine Vandenplas, Bsc – UCB Biopharma SRL; Christian Wolff, PhD – UCB Biopharma SRL; Brittany Vallette, PhD – UCB Biopharma SRL; Stefanie Dedeurwaerdere, PhD – UCB Biopharma SRL
Rationale: The solute carrier family six member 1 (SLC6A1) gene encodes GABA transporter 1 (GAT-1), which is one of the main transporters in the central nervous system that reuptakes GABA. It is highly expressed in presynaptic inhibitory neurons and astrocytes. Mutations in SLC6A1 leading to reduced GABA re-uptake that have been recently identified in humans and the associated phenotypes are myoclonic-atonic epilepsy, absence epilepsy, autism and neurodevelopmental delay. In most of the cases, phenotype occurs early in life. Recent evidence indicates that partial or complete loss-of-function is the major pathology for the mutations across phenotypes. To progress towards effective treatments, development of preclinical models of SLC6A1 encephalopathies are needed. Therefore, we decided to investigate cortical EEG and behavior of a transgenic mouse model bearing the patient-derived SLC6A1 S295L mutation. This mutation was recently identified as a cause of developmental and epileptic encephalopathy.
Methods: Male heterozygous SLC6A1+/S295L mice and their wild type littermates were used in this study. Continuous wireless telemetry recordings of cortical EEG combined with video monitoring were performed for several weeks to detect seizures by using a proprietary automated detection software. A battery of neurobehavioral tests was performed to evaluate any potential deficits in gross locomotor activity, motor coordination, muscle tone, muscle strength or cognitive performances. LC-MS/MS methods were performed from brain homogenates to measure total GABA levels in different brain structures including thalamus, hypothalamus, cortex, striatum, hippocampus, cerebellum, olfactory bulb and brain stem.
Results: All SLC6A1+/S295L mice displayed spike wave discharges (SWDs) which occurred in a circadian pattern during a 12h:12h light–dark cycle. Behavioral tests failed in detecting a phenotype in SLC6A1+/S295L mice compared to their WT littermates. Total GABA levels measured in brain homogenates from different brain structures were identical between the mutant and WT mice.
Conclusions: While the behavior phenotype and total brain GABA levels remained unchanged, the SLC6A1+/S295L mice showed robust and typical SWDs reminiscent of the human disease and thus provides a relevant preclinical model for evaluating disease modifying therapies.
Funding: Research was funded by UCB Biopharma SRL.