Peter A.V. Anderson, Ph.D., Retired
Using Evolution to Understand Our Nervous System
Former Director of the Whitney Laboratory, 1996 – 2012; Professor of Physiology and Functional Genomics, Neuroscience and Biology.
Dr. Peter Anderson graduated with a B.S. in zoology from St. Andrews University in Scotland with First Class Honours. He earned his M.A. and Ph.D. in biology at the University of California, Santa Barbara and did his postdoctoral research with Dr. George Mackie at the University of Victoria in British Columbia, Canada.
Jellyfish and related animals have nervous systems and even brains and it is rather humbling to realize that their nervous systems and brains work in very much the same way as our own. Their’s are obviously much simpler, with far fewer nerve cells and far fewer connections between those nerve cells – which is where our brain’s complexity comes from – but the basic mechanisms that determine how our brains function are very much the same as those in jellyfish.
Why is this? Because the molecules and mechanisms that allow our brains to function the way they do have evolved over many hundreds of millions of years and the starting point in that evolution was in the nervous system of something like a jellyfish. Thus, modern-day jellyfish give us a window into what the earliest nervous system might have looked like and how its component molecules functioned – the starting point in the long evolutionary history that molded our nervous system and brain. Only by knowing where our nervous system came from, in the evolutionary sense, can we truly understand why our brain and its myriad of molecules work the way they do.
Nervous System Evolution – Research Description
The focus of research in my lab is neuroscience, particularly the evolution of the nervous system and understanding the fundamental principles of nervous system function that can be gleaned from some of the earliest nervous systems we know of. Most of our research has been carried out with cnidarians, because they represent some of the earliest nervous systems and, most importantly, because they provide useful preparations for detailed electrophysiological analysis of electrogenicity and synaptic transmission. For example, in the the jellyfish Cyanea capillata (Class Scyphozoa) (Fig. 1), neurons in the motor nerve net (MNN) are large enough for intracellular recording, including voltage clamp analysis, allowing us to examine the physiology and pharmacology of the “early” nervous system. Moreover, synapes between MNN neurons are also readily accessible and amenable to intracellular recording, enabling chemical synaptic transmission to be examined in considerable detail. We are currently taking advantage of these features of this preparation to identify the neurotransmitter at these synapses.
At the same time, the phylogenetic separation between cnidarians and mammal provides a novel way of addressing the relationship between structure and function of specific molecules, including ion channels. In some instances, the function of ion channels and their subunits is highly conserved in both cnidarians and mammals. Under these circumstances, one can ignore structurally different parts of the molecule when trying to map function to structure. Alternatively, some functions, particularly pharmacology, are not conserved between cnidarians and mammals. In these cases, structural differences between the cnidarian and mammalian proteins can be used to identify drug binding sites and other functions. In both instances, the information provided by the breadth of the phylogenetic comparison allows the “noise” normally present in comparisons of protein structure to be separated from the “signal”. Work in this broad area remains an on-going interest in my lab.
Another interest that emerged from our work with cnidarians is directed at one of the most fascinating and arguably most complex cell in any eukaryote, the cnidarian cnidocyte, or sting cell. In some cnidarians, cnidocytes are electrogenic, and in all they are effectors whose activity is regulated, in part, by synaptic input from the animal’s nervous system.
1. Identity of the neurotransmitter at MNN synapses. Despite the amount of progress that has been made over the last 20 years in understanding the properties and capabilities of the cnidarian nervous system, one aspect of neuronal function that we still know relatively little about is the identity of neurotransmitters used by these animals, particularly the presence and role of the non-peptidergic neurotransmitters that are so prevalent in other nervous systems. While there is little doubt that neuropeptides are present, abundant and active in cnidarians of all classes, a variety of reports suggest that more traditional neurotransmitters may also be present in cnidarians.
We have been taking advantage of the fact that MNN neurons and their synapses can be completely exposed (Figure 2) to study the action of a variety of neurotransmitter candidates, including those typically associated with fast synapses in higher animals, on synapses in the MNN. Only the amino acids taurine and beta-alanine produce physiological responses consistent with those of the normal EPSP in these cells. Moreover, chemical analysis has revealed that both taurine and beta-alanine are present in the neurons and released by depolarization. These findings strongly suggest that either or both of these amino acids, or a closely related compound is the neurotransmitter at synapses between MNN neurons. Current research is using a combination of Capillary Electrophoresis (CE), molecular biology and receptor binding to identify candidate neurotransmitters released from the synaptic areas by electrical activity, to identify and characterize receptors for the neurotransmitter, and identify the mechanisms, such as uptake, used to remove the neurotransmitter from the synapses. This rather traditional approach is the one that is most likely to unequivocally identify the neurotransmitter at one of the earliest, fast chemical synapses. It may also provide good insight into chemical neurotransmitter pathways, in general and their evolution in particular.
2. Regulation of cnidocyte discharge. The cnidocytes of jellyfish and other cnidarians are extremely complex cells whose primary function is discharge. This process is regulated by a combination of very specific chemical and mechanical stimulation. We have been using a combination of electrophysiology, cell and molecular biology, including transcriptomic work, to understand the factors and cellular components that are involved in the regulation and mechanism of cnidocyte discharge.
3. Ion channels in cnidocytes. We have cloned a variety of voltage-gated ion channels from cnidocytes of the Portugese Man-of-War, Physalia physalis. These included fragments of a Ca 2+ channel alpha-1 subunit, a complete Ca2+ channel beta subunit (PpCavbeta) and a Shaker-like K+ channel (PpKv1). The functional properties of the latter two channel proteins were characterized electrophysiologically using heterologous expression.
While the presence of Ca2+ channel subunits in cnidocytes supports the model that discharge is a Ca2+-dependent exocytotic event, this finding must be interpreted cautiously. There is functional evidence that cnidocytes can form the pre-synaptic element of chemical synapses. Thus, Ca2+ channels are likely to be present in the cells, but localized near the basal membrane, where the synapses are located, rather than theapical membrane where discharge occurs. This distinction is important to our understanding of the Ca2+-dependency of cnidocyte discharge.