Functional screening of neuro-pharmaceuticals with neuronal cell cultures

"The brain is dynamically organized into cellular populations, ...which act as functional units."
(GM Edelmann, 1987)

"Neuronal Networks are the fundamental unit of functional organization."
(RJ McGregor, 1987)

The architecture of neuronal information processing can be perceived as being organized in three levels: cellular processing, communication between cells, and functions expressed by whole networks. Measurements of electrophysiological characteristics are necessary to understand each of these levels.

NeuroProof has optimised biosystems technology to study electrical activity patterns of neuronal networks on multielectrode arrays (MEA-neurochips) as functional Screening. In this system, cells or tissues are grown directly on the chip surface and communicate via chemical and electrical signals. The MEA-neurochip allows the non-invasive, long-term, multisite recording of electrical signal patterns of primary neuronal networks. The MEA-neurochip technology enables the characterisation of network activity pattern on the single-cell action-potential level and on the level of complex neuronal networks as the basic functional units.

Therefore, spontaneously active monolayer networks on MEA-neurochips offer great potential for studying:

• neuronal network development,
• generation of spatio-temporal action potential patterns,
• strategies of pattern processing and storage,
• possible optimization processes of network structure and function

They also act as test systems to investigate neuro-physiological properties of compounds that are technically difficult or impossible to obtain in vivo. Despite the complexity, the neurophysiological action profiles of neuroactive compounds are sensitive and selective as well as robust and stable, allowing a precise pharmacological "fingerprinting" and the creation of a database of information on well-characterized neuroactive substances.

The complex description of the changes caused by treatment of a neuronal network co-cultured with glia allows a sophisticated approach to quantify the complex effects of neuroactive agents, of unknown compounds, and of complex mixtures. Our analysis provides multiparametric information on neuronal activity changes to assess the therapeutic potential of neuroactive drugs. The NeuroProof-technology will deliver crucial findings for the development of CNS drugs in coming years.

With the technology framework Pattern Expert, an advanced data analysis tool for pattern recognition, the influence of compounds on electrical activity patterns can be studied and interpreted. The basic precondition is the ability to reproduce experiments, which can be shown with the help of our newly developed data analysis tools. Furthermore, it was shown that every compound has its own fingerprint it changes the network activity pattern in a specific way.

Pharmacologists are provided with a universal model to study neuronal activity under the influence of newly developed substances and drug candidates. This method supplements brain slice culture and patch clamp technology. It provides a completely new insight into opportunities of drug development not seen until now. A wide range of phenomena within activity patterns can now be studied precisely, e.g., synchronicity between individual nerve cells can be quantified with new measures. Now we can differentiate between "physiological" and "side" effects.