Neuropharmacology

Biography

Biography: Enzo Wanke

Abstract

Study of neurodegenerative disease pharmacology is complicated because investigating drug effects on CNS activity in vivo is time-consuming and expensive. Recent advances in extracellular multi-site recording methods, where signals can be recorded for weeks from functional ex-vivo cortical networks, allows us to test drug effects more directly, and to obtain dose-response data over a longer time-frame. This is important, because normal CNS activity in vivo is disrupted if astrocytes do not sustain their fast [K+]o spatial buffering capacity and ultrafast glutamate uptake processes, but also if microglia are not in a healthy condition. We used neuron/astrocyte/microglial cortical networks to examine the effects of a mild sterile inflammation induced by the bacterial endotoxin lipopolysaccharide (LPS), which significantly modulated neuronal excitability and initiated atypical burst-firing events resembling epileptiform seizures, a recognized feature of various CNS neurodegenerative. We simultaneously analyzed the reverberating bursting activity of a ten thousand neuron network recorded with a multi-electrode array (MEA). This change in excitability was blocked by pre-treatment with various anti-nflammatory drugs and was also sensitive to pM proinflammatory cytokines. Since neuroinflammatory components are involved in a wide range of neurodegenerative, neurological, and psychiatric CNS disorders, we suggest that our methodology might be a useful tool to rapidly screen novel anti-inflammatory/neuroprotectant molecules. The fact that we can detect and analyse long-term effects on neuron activity during microglial activation also opens the possibility to study recently demonstrated roles of “resting” microglia, probably bi-directionally cross-talking with neurons in the developing CNS.