P2DS

The search for neuroactive substances that can be used therapeutically is accompanied by a high rate of exclusion of drug candidates. The new test platform is intended to help reduce this exclusion rate. Various test methods are combined for this purpose: behavioral tests in animal models, microelectrode arrays and RNA interference methods. Post-traumatic stress disorders serve as an example in a feasibility study.

The project aims to develop a novel, predictive, preclinical screening platform to reduce the prevailing high exclusion rate of drug discovery for psychiatric disorders. The development of new devices for drug testing is linked to the establishment of a standardized in-vivo model. Neuronal activity is measured using electrophysiological methods and activity patterns are compared in vitro and in vivo. Compared to conventional systems, additional specificity is achieved through the use of RNA interference methods both in vitro and in vivo. The approach is generally applicable to many questions. In this project, a feasibility study is carried out using the example of post-traumatic stress disorders, in which the GABA-A receptors play a specific role and represent challenging target structures for drug discovery.
Specifically, microelectrode arrays are used to record signals from rats in vivo, whose behavior in stress paradigms is measured in parallel with the recording. The results are compared to those of conventional electrophysiological methods. In parallel, networks of cultured cortical neurons on microelectrode arrays are derived in vitro in order to compare in vivo data with those from much higher throughput in vitro systems. Individual GABA-A receptors will be downregulated by lentiviral delivery of RNA interference vectors to study the involvement of specific receptor subunits in behavior and synaptic function and for drug specificity both in vitro and in vivo. Finally, these vectors are also used to characterize the changes in synaptic structures in the experimental approaches.