Effects of excitation on the metabolism of a simple neuronal system: the mammalian sympathetic ganglion

Abstract When studying the effects increased neuronal activity may have on metabolism it is important to have a well-defined morphological and neurophysiological preparation. The mammalian sympathetic ganglia are “relatively simple” neuronal preparations which have been the subject of numerous pharmacological, physiological, and biochemical studies. The superior cervical ganglion, in particular, has drawn the most attention. This ganglion is readily accessible for in vitro and in vivo experiments and the physiological activity of this preparation can be carefully controlled by the experimenter. Even though the mammalian sympathetic ganglion is considered to be a relatively simple preparation, our knowledge of the type of cells within the ganglion and the neuronal connections is far from complete (section 2.2). The postganglionic cell bodies in the superior cervical ganglion are considered to be noradrenergic (sections 2.2 and 8). Interneurons are also present in these ganglia; they have been characterized as small intensely fluorescent cells which appear to contain (and release) either norepinephrine or dopamine or both (sections 2.2 and 9.1). These interneurons form synapses on the postganglionic noradrenergic neurons. The type or types of interneurons found within the superior cervical ganglion may be species dependent. A high proportion, but not necessarily all, of the fibers in the preganglionic trunk release acetylcholine. These cholinergic fibers appear to form synapses on the postganglionic noradrenergic cells as well as on the interneurons (sections 2.2, 2.3, and 7). The types of synapses observed in a mammalian sympathetic ganglion appear to include the entire spectrum of possibilities, e.g. axoaxonic, axodendritic, etc. (Elfvin, 1963a, b; 1971). Even presented in these simple terms the neuronal connections within the ganglion are complex. In addition, the glial cell population has to be taken into account when trying to interpret data. The extent to which the functions of the glial cells and neurons are coupled are largely unknown. Consequently, in certain cases, strict interpretations of biochemical events as occurring solely within neurons should be made with some caution. However, with the use of certain pharmacological agents and neurophysiological measurements, various investigators have presented strong evidence which indicates that certain alterations in metabolism as related to the excitability of the nerve tissue preparations are occurring in neurons. The viability of mammalian sympathetic ganglia is dependent upon a sufficient source of glucose and oxygen (sections 3.1 and 3.2). Glucose is important for supplying precursors to certain biosynthetic pathways (e.g. glycine, glutamate, acetylcholine, etc.) and for oxidation to provide high energy compounds (e.g. ATP). Electrical stimulation of the preganglionic fiber of the superior cervical ganglion of the rat increases the uptake and utilization of both glucose and oxygen (section 3.1). With glucose as the sole external carbon source, this ganglion can maintain a steady carbon and energy balance for long periods of increased neuronal activity. Removal of glucose from the media results in a loss of synaptic transmission; prolonged absence of glucose results in an irreversible loss of transmission and severe morphological damage to presynaptic structures (section 3.1). The increased uptake of glucose in stimulated ganglia may be a result of increased needs for certain biosynthetic pathways (e.g. supplying the acetate moiety for synthesis of acetyl CoA, one of the precursors for acetylcholine synthesis) and increased demands on its energy stores. For example, the re-establishment of the ionic gradient across neuronal membranes and the reuptake of released choline (as acetylcholine) and catecholamines are both energy-demanding processes. The rate of acetylcholine synthesis and release as well as choline uptake and utilization are greater in stimulated than in resting ganglia (section 7.1). It has also been shown that acetylcholine synthesis is dependent upon glucose being present, and occurs only under aerobic conditions (section 7). The metabolism of norepinephrine in cell bodies within the ganglion does not appear to be affected by acute periods of increased neuronal activity, whereas at the nerve endings increased activity appears to increase the metabolism of this catecholamine (section 8). There is an ever-increasing body of evidence which indicates that cyclic AMP is involved in the regulation of metabolism and physiological function in the nervous system. Stimulation of the preganglionic trunk of the rabbit superior cervical ganglion significantly increases the ganglionic levels of cyclic AMP (section 9.1). With the use of cholinergic blocking agents such as atropine and hexamethonium and α-adrenergic antagonists, such as phentolamine, evidence was obtained (Kebabian and Greengard, 1971; McAfee et al. , 1971) which suggested that the increased cyclic AMP levels were a result of the release of catecholamines from the interneurons. In the case of the rabbit superior cervical ganglion, the catecholamine released appeared to be dopamine (section 9.1). However, it is not possible to determine if cyclic AMP increased only in neurons or if the increase was happening in both glia and neurons. In the case of the rabbit superior cervical ganglia, additional electrophysiological evidence was presented (Kebabian and Greengard, 1971) which suggested that cyclic AMP played a direct role in the mediation of dopaminergic transmission. Studies on specific effects of excitation on ganglionic protein and RNA metabolism are far from conclusive. Acute periods of stimulation appear to decrease the synthesis of protein in rat and guinea-pig superior cervical ganglia (section 6.2). This may be caused by a shifting of available ATP from this biosynthetic pathway to meet other increased energy demands. A very interesting observation is the increased synthesis of phosphatidyl inositol found in stimulated ganglia (section 4.2). This appears to be a specific affect associated with the interaction of acetylcholine with the postsynaptic membrane since: (a) acetylcholine alone can elicit this response; (b) the response due to electrical stimulation of the preganglionic fiber is blocked by d -tubocurarine; (c) antidromic stimulation fails to produce this increase; and (d) this effect is not seen in stimulated peripheral nerve where there are no apparent synapses present. The subcellular site of this increased labeling was examined (Burt and Larrabee, 1973) and one-third or more of the increase was associated with the synaptosomal (nerve ending) fraction and one-third or more with the mitochondrial fraction. However, because of the relative impurity of the fractions, the specific site or sites of the increased labeling could not be definitively stated. In conclusion, the mammalian sympathetic ganglia is a preparation that can be simultaneosly studied, under carefully controlled experimental conditions, from two or more different scientific viewpoints. Such studies have the advantage of supplying to the neuroscientist data which can potentially be cross-correlated from one field to another and thereby provide, in a more critical manner, information which could give a clearer insight into the relationship between the specialized functions of nerve cells and their biochemical characteristics.