Relevance of Excitable Media Theory and Retinal Spreading Depression Experiments in Preclinical Pharmacological Research

Abstract

In preclinical neuropharmacological research, molecular, cell-based, and systems using animals are well established. On the tissue level the situation is less comfortable, although during the last decades some effort went into establishing such systems, i.e. using slices of the vertebrate brain together with optical and electrophysiological techniques. However, these methods are neither fast, nor can they be automated or upscaled. By contrast, the chicken retina can be used as a suitable model. It is easy accessible and can be kept alive in vitro for hours up to days. Due to its structure, in addition the retina displays remarkable intrinsic optical signals, which can be easily used in experiments. Also to electrophysiological methods the retina is well accessible. In excitable tissue, to which the brain and the retina belong, propagating excitation waves can be expected, and the spreading depression is such a phenomenon. It has been first observed in the forties of the last century. Later, Martins-Ferreira established it in the chicken retina (retinal spreading depression or RSD). The electrophysiological characteristics of it are identical with those of the cortical SD. The metabolic differences are known and can be taken into account. The experimental advantage of the RSD compared to the cortical SD is the pronounced intrinsic optical signal (IOS) associated with the travelling wave. This is due to the maximum transparency of retinal tissue in the functional state; thus any physiological event will change it markedly and therefore can be easily seen even by naked eye. The theory can explain wave spread in one (action potentials), two (RSDs) and three dimensions (one heart beat). In this review we present the experimental and the excitable media context for the data interpretation using as example the cholinergic pharmacology in relation to functional syndromes. We also discuss the intrinsic optical signal and how to use it in pre-clinical research.

The Plastic Glial-Synaptic Dynamics within the Neuropil: A Self-Organizing System Composed of Polyelectrolytes in Phase Transition

“…Out of seven retinas submitted to liquid deuterium, two (from the same animal) were dead within the hour. Both displayed the typical excitotoxic optical profile before tissue death (see [ 18 ]). The other five became unstable and developed “spontaneous” activity [ 29 ], in which the optical profiles also changed from wave to wave.…”

“…In this avascular retina, the metabolism depends one hundred percent on anaerobic glycolysis performed in the glia [ 45 ]. Moreover, there is tight coupling between the rate of ion transport and the production of lactate by glia (for details and relevant literature, see [ 18 , 45 ]). The consequence of stopping ion transport is a halt in metabolism and subsequent change in the ATP/ADP ratio.…”

“…All 10 retinas were dead within one to two hours of exposition to ouabain. In this series of experiments, we could distinguish two pathways to tissue death: an acute cell lysis that has the appearance of a macroscopic edema [ 18 , 45 ] and a second type of evolution to death (apoptosis?) without the edema.…”

“…At the lowest concentration of 10 nM, the onset of the excitotoxic response had a latency of 30 minutes whereas the onset was 20–30 seconds with 1 mM. The nanomolar concentration range is the hormonal range and indeed the hypothalamus and suprarenal glands produce cardiac glycosides (see references at [ 18 , 44 ]). It happens that the β subunit of the glia ATPase is an adhesion molecule [ 46 , 47 ].…”

“…The presence of remarkable intrinsic optic signals (IOS) in retinal grey matter adds a new dimension to these studies. Two recent publications give a detailed description of the retinal IOS and how to use it in research [ 17 , 18 ].…”