In the touchscreen test, there is about a 10–15% difference in cognitive deficit along the reversal learning process between the wild type and CVN mice. Is this effect robust enough to predict the efficacy of a molecule?
The CVN mice show statistically significant impairment compared to wild type even though the difference is not very large (10–15%). Having two CVN mice cohorts—a vehicle-treated group and a compound-treated group—would ensure that the phenotype of impaired cognition is reproduced in the vehicle-treated CVN mice. This would result in a reproducible reversal learning graph. The reversal learning (visual discrimination) resembles dimensional human touchscreen testing tasks that are commonly used to assess cognitive impairment so the similarity between rodent touchscreen testing and human touchscreen testing increases the translational index.
Which behavioral deficits are reproducible in CVN mice and are the deficits responsive to treatment?
In CVN mice, the motor deficit is reproducible but is used more as a biomarker endpoint and less to assess efficacy. The cognitive deficit is also reproducible and is used more to assess efficacy using fear conditioning, the Barnes maze or the radial arm water maze. Unfortunately, while the CVN mice have been used extensively, the deficit response to several neuroprotective drugs has not been very successful.
Has Charles River tested therapeutic compounds in CVN mice?
Recently, we validated the CVN mouse model and the next step is to test therapeutic compounds on the CVN mice. We will be testing several options, including treating the animals and then performing electrophysiology tests, and using compounds to study differential effects on synaptic transmissions in wild-type or diseased animals.
Are there non-rodent models available for AD studies?
Large animals have been used to assess cognition using touchscreen technologies. Either aged or scopolamine-treated animals (to impair cognition) are used for touchscreen and biomarker assessment of cerebrospinal fluid (CSF). Currently, Charles River Finland only has rodent capabilities.
Is there a benefit to using the radial arm water maze instead of the standard reference Morris water maze?
No. One test does not have a significant benefit over the other and both tests are run routinely.
For electrophysiology studies, which parameters would you recommend be investigated?
We suggest not only looking at long-term potentiation but also at the amplitude of basal synaptic transmissions. In AD models, the basal synaptic transmission tends to get disrupted, making it easier to detect those changes compared to long-term potentiation changes.
Is it necessary to have a high sample number to address the variability that can cause an impact on statistical significance in drug testing studies?
No. In multiple blind studies, we have found similar results in small and large groups of mice.