Development of high-throughput, non-invasive behavioural and cognitive tests in mice to uncover new mechanisms of abnormal cognition and behaviour

• Main Author: Stewart, Michelle Elizabeth
• Published: Open University 2018
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.765594

Cognition is a complex process encompassing a variety of traits, including the ability learn, remember, evaluate situations, make decisions and solve problems. Research over recent decades has begun to elucidate some of the mechanisms through which organisms carry out these complex behaviours, however there is a great deal that is not understood about the basic biology of cognition. Importantly, there is a deficit in our knowledge not only of the underlying biology but also the pathological mechanisms which lead to cognitive disease. Genetically altered mice have been developed that model some aspects of cognitive disease. However at present these models have helped to elucidate only certain elements of cognitive processes and many have had limited use in drug development. To further understand cognition and cognitive disease, as well as develop effective treatments, it is critical to have more genetically altered mouse lines that better model the human condition. To find such models we have employed a high-throughput screening approach. Firstly we assessed existing behavioural and cognitive tests for their suitability to high-throughput testing, we then incorporated the selected test, fear conditioning, into a high-throughput pipeline. 289 different genetically altered (GA) lines were screened using the fear conditioning protocol and GA lines with potentially interesting phenotypes selected for further analysis. Using this screening process Ferric chelate reductase 1-like (Frrs1l) was selected for more in-depth testing. On further investigation we found deletion of Frrs1l to cause increased neonatal mortality and abnormalities in activity, co-ordination, muscle strength, cognition and body weight, as well as seizures. These phenotypes appear to be caused by a dramatic reduction in AMPA receptor levels at the synapse, as well as mislocalisation of AMPA receptors and alterations in processing. In collaboration with clinicians we corroborated these findings with some newly identified patients with homozygous mutations in FRRS1L.