Synaptic Plasticity and the Modulation of the Ca2+ Current

Abstract

The study of the mechanisms of neuronal plasticity and the attempt to relate these mechanisms to actual instances of learning has accelerated in recent years as a result of the application of the techniques of biophysics and cell biology to central neurones and their interconnexions. Although support for it has been obtained only recently, the idea that learning might involve changes in the effectiveness of the connexions between neurones actually had its origins at the turn of the century. Following an earlier suggestion by E. Tanzi (1893), Ramon y Cajal postulated, in his Croonian Lecture to the Royal Society of London in 1894 (a lecture to which he was invited through the intervention of Charles Sherrington), that learning might involve changes in strength of connexions between neurones. An almost identical idea was put forth by Sigmund Freud also in 1894 in a fragmentary manuscript published only in 1950. A first requirement of this postulate is that some synapses have plastic properties, that they can change their efficacy following simple use or following more complex patterns of stimulation. This basic requirement has now been fully satisfied. A variety of experiments have shown that chemical synapses can undergo changes in effectiveness as a result of activity or inactivity in a given pathway (homosynaptic change) or as a result of activity in other pathways (heterosynaptic change). Some of the best evidence has come from studies of simple synaptic systems such as the synapses between vertebrate motor neurones and skeletal muscle (for reviews, see Katz, 1962; Eccles, 1964; Kandel & Spencer, 1968).Soon after the initial discovery of the end-plate potential by Gopfert & Schaefer (1938), Schaefer, Scholmerich & Haass (1938) and subsequently Feng (1941) found that repeated (tetanic) stimulation increased the amplitude of the end-plate potential without producing any obvious changes in the action potential of the presynaptic axon. The increase in the end-plate potential was not restricted to the period of tetanic stimulation but persisted for several minutes after the tetanus. Feng called the synaptic enhancement that persisted after the tetanus post-tetanic potentiation. He also found that longer tetani produced greater potentiation than did shorter ones. In 1947, Larrabee and Bronk found post-tetanic potentiation at a peripheral neurone-to-neurone synapse between preganglionic and postganglionic cells of the stellate ganglion. In 1949, Lloyd described similar potentiation in the monosynaptic reflex of the spinal cord, thereby showing that these plastic changes also occur in central neurones. Lloyd found (as had Larrabee and Bronk) that post-tetanic potentiation produced by stimulating one afferent pathway did not increase the response of the postsynaptic cell to synaptic activation via another, unstimulated, afferent pathway. These experiments indicated that post-tetanic potentiation is homosynaptic: it is restricted to the stimulated pathway and results from a change in the synapse itself. Lloyd (1949) also described a second type of plastic change when he found that low frequencies of stimulation produced a decrease in synaptic effectiveness. This form of plastic change he called low-frequency or homosynaptic depresssion.Analysis remained at this stage for a number of years because it was difficult to determine whether these changes were due to a presynaptic mechanism (a change in transmitter release) or to a postsynaptic mechanism (a change in receptor sensitivity). The solution to this problem was facilitated in 1954 when del Castillo & Katz (1954a) demonstrated that release of acetylcholine at the nerve muscle synapse is not graded but quantized. An action potential releases about 200 multimolecular packets of transmitter-called quanta -and each quantum contains several thousand molecules of ACh. Quantal transmission was soon found to be the general mode of transmitter release at chemical synapses (see Dudel & Kuffler, 1961a; Eccles, 1964). The discovery of quantal transmission not only established important new insights into the nature of transmitter release from the terminals but also provided a method for analysing the relative contribution to synaptic transmission of changes in presynaptic and postsynaptic mechanisms. Del Castillo & Katz (1954a, b), Liley (1956a, b) and subsequently others, analysed alterations in synaptic effectiveness in terms of quantal transmission and found that both homosynaptic depression and post-tetanic potentiation represented a presynaptic alteration in the number of transmitter quanta released per impulse. The sensitivity of the receptor seemed not to be affected.This work was extended in a major direction in 1961 when, following the earlier suggestion of Frank & Fuortes (1957), Dudel and Kuffler described the first clear instance of a heterosynaptic interaction : presynaptic inhibition at the crayfish nervemuscle synapse. Dudel & Kuffler (1961a) found that in the crayfish the inhibitory axon to muscle has a double function: (1) it produces an inhibitory postsynaptic potential in the muscle, and (2) it depresses the excitatory postsynaptic potential produced by the excitatory axon. By applying a quantal analysis Dudel & Kuffler (19616) found that presynaptic inhibition reduces the number of transmitter quanta released by the excitatory axon without affecting the sensitivity of the receptor molecules. These experiments provided the first evidence that the membrane of the presynaptic terminals contains receptors to transmitter molecules, and that these receptors can control transmitter release. Subsequently, Kandel & Tauc (1964), Epstein & Tauc (1970), and Castellucci and his colleagues (1970) presented suggestive evidence for presynaptic facilitation of transmitter release in the synapses of Aplysia. Recently again based upon a quantal analysis, Castellucci & Kandel (1976) provided direct evidence for a presynaptic mechanism.In 1967 Katz and...