Better knowledge of what causes nervous disorders, and the possible worsening of symptoms, will aid the future development of better treatments.
Rationale
Nervous disorders include neurodevelopmental disorders, such as autism, and neurodegenerative disorders, such as Alzheimer's disease. Although they have different characteristics, the first sign that something is wrong is often a change in behaviour. These conditions can be difficult to treat with currently available medications, but better knowledge of what causes each nervous disorder, and the possible worsening of symptoms, will help scientists to develop better treatments. One way that scientists are gaining a better understanding of what causes the brain to function abnormally in nervous disorders is through the use of DNA sequencing to identify genetic variants in patients that are absent from healthy individuals.
Plan of work and impact of our studies
We will breed genetically altered mice that harbour genetic variants shared with nervous disorder patients and compare their behaviour with normal mice. Typically, mice will be subject to up to eight behavioural tests, including tests of locomotor activity and exploration, anxiety-related behaviours, learning and memory, social interaction, depression-related behaviours, motor function, and attention. To assess disease progression, four of the eight tests may be repeated no more than twice. To quantify the effects of epilepsy-associated genetic variants on susceptibility to seizures, mouse strains harbouring them will be subject to procedures that may induce seizures. If a genetically altered mouse strain exhibits abnormalities that replicate symptoms exhibited by human patients, we may subsequently use it to test preventative or therapeutic strategies. Occasionally, mice may be subject to a surgical procedure for recording electrical signals during sleep and seizures, or for collection of neurochemicals from discrete parts of the brain. Published scientific articles and presentations to scientific conferences and patients' groups are expected to emerge from new information gained on how genetic alterations pertaining to human nervous disorders affect brain structure/function and behaviour.
Animal welfare and the three Rs
Replacement
It is difficult to carry out the necessary experiments in humans to determine the effects of a genetic variant on brain function because there are strict limitations on human studies. Our approach is to introduce the genetic variant into mice, and study its effects on their brain and behaviour.
Reduction
There will be a limit on the total number of behavioural tests and the number of aversive stimuli given to any one animal. At the end of testing, each mouse will be humanely killed, and its brain and organs collected for further analysis.
Refinement
Before behavioural testing, mice will be handled to reduce the stress of human interactions. Tests involving electric shock will only be used at the end of the series of tests if milder tests of learning and memory do not achieve the desired outcome. Genetically altered mouse strains with visible neurological defects will not be given electric shocks. Good handling and injection technique will minimise any minor/brief distress associated with the systemic administration of test substances. The procedures to assess seizure susceptibility will be completed within one hour and are designed to induce seizures only in mice with an increased susceptibility to seizures, not in wild-type control animals. Any animal showing persistent signs of pain or distress will be humanely killed to prevent further suffering.