1. The after-effects of repetitive stimulation of the perforant path fibres to the dentate area of the hippocampal formation have been examined with extracellular micro-electrodes in rabbits anaesthetized with urethane.2. In fifteen out of eighteen rabbits the population response recorded from granule cells in the dentate area to single perforant path volleys was potentiated for periods ranging from 30 min to 10 hr after one or more conditioning trains at 10-20/sec for 10-15 sec, or 100/sec for 3-4 sec.3. The population response was analysed in terms of three parameters: the amplitude of the population excitatory post-synaptic potential (e.p.s.p.), signalling the depolarization of the granule cells, and the amplitude and latency of the population spike, signalling the discharge of the granule cells.4. All three parameters were potentiated in 29% of the experiments; in other experiments in which long term changes occurred, potentiation was confined to one or two of the three parameters. A reduction in the latency of the population spike was the commonest sign of potentiation, occurring in 57% of all experiments. The amplitude of the population e.p.s.p. was increased in 43%, and of the population spike in 40%, of all experiments.5. During conditioning at 10-20/sec there was massive potentiation of the population spike (;frequency potentiation'). The spike was suppressed during stimulation at 100/sec. Both frequencies produced long-term potentiation.6. The results suggest that two independent mechanisms are responsible for long-lasting potentiation: (a) an increase in the efficiency of synaptic transmission at the perforant path synapses; (b) an increase in the excitability of the granule cell population.

/pdf/long-lasting-potentiation-of-synaptic-transmission-in-the-418ev0n9w7.pdf

Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path.

▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

/pdf/short-term-synaptic-plasticity-5d4dx79319.pdf

Short-Term Synaptic Plasticity

One of the most remarkable aspects of an animal's behavior is the ability to modify that behavior by learning, an ability that reaches its highest form in human beings. For me, learning and memory have proven to be endlessly fascinating mental processes because they address one of the fundamental features of human activity: our ability to acquire new ideas from experience and to retain these ideas over time in memory. Moreover, unlike other mental processes such as thought, language, and consciousness, learning seemed from the outset to be readily accessible to cellular and molecular analysis. I, therefore, have been curious to know: What changes in the brain when we learn? And, once something is learned, how is that information retained in the brain? I have tried to address these questions through a reductionist approach that would allow me to investigate elementary forms of learning and memory at a cellular molecular level-as specific molecular activities within identified nerve cells.

/pdf/the-molecular-biology-of-memory-storage-a-dialogue-between-2cym9imp74.pdf

The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses

Various applications of pAx measurements are discussed based on the hypothesis that drugs and drug antagonists compete for receptors according to the mass law. Examples are given illustrating the use of pAx measurements to identify agonists which act on the same receptors and to compare the receptors of different tissues. Tests of competitive and noncompetitive antagonism are considered in relation to the antagonisms acetylcholine-atropine, histamine-atropine and acetylcholine-cinchonidine. A new measure, pAh, is introduced to express the activity of unsurmountable antagonists.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1959.tb00928.x

Some quantitative uses of drug antagonists

Interneurons of the hippocampus

In this paper a further study is made of the spontaneous synaptic potentials in frog muscle (Fatt & Katz, 1952a), and their relation to the end-plate response. It has been suggested that the end-plate potential (e.p.p.) at a single nerve-muscle junction is built up statistically of small all-or-none units which are identical in size with the spontaneous 'miniature e.p.p.'s'. The latter, therefore, could be regarded as the least unit, or the 'quantum', of end-plate response. A convenient picture of how hundreds of such quanta, each capable of producing a miniature potential of 0 5-1 0 mV, can build up an e.p.p. of, say, 70-80 mV is provided by the hypothesis that separate parcels of acetylcholine (ACh), released from discrete spots of the nerve endings, short-circuit the muscle membrane. The unit changes of membrane conductance produced at many parallel spots summate and lead to an intense depolarization of the muscle fibre. Although this is a plausible view, there is no direct proof that the normal e.p.p. is made up in this quantal fashion. The evidence comes from experiments in which the 'quantum content' of the e.p.p. had been reduced to a small number by lowering the external calcium concentration (Fatt & Katz, 1952 a). It was then found that the size of the end-plate response approached that of the spontaneous potential and at the same time exhibited large random fluctuations, apparently involving steps of unit size. Similar observations were made by Castillo & Engbaek (1954) on muscles treated with Mg-rich solutions. The statistical behaviour of the end-plate response under these conditions has been investigated in more detail and subjected to a quantitative analysis.

Quantal components of the end-plate potential

The present study arose from the chance observation that end-plates of resting muscle fibres are the seat of spontaneous electric discharges which have the character of miniature end-plate potentials. The occurrence of spontaneous subthreshold activity at an apparently normal synapse is of some general interest, and a full description will be given here of observations which have been briefly reported elsewhere (Fatt & Katz, 1950a).

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1952.sp004735

Spontaneous subthreshold activity at motor nerve endings

1. The hypothesis is put forward that a residue of the ;active calcium' which enters the terminal axon membrane during the nerve impulse is responsible for short-term facilitation.2. This suggestion has been tested on the myoneural junction by varying the local calcium concentration so that during the first of two nerve impulses [Ca](o) is either much lower than, or raised to a level approaching that, during the second impulse. Facilitation is much larger in the latter case, which is in accordance with the ;calcium hypothesis'.3. A short pulse of depolarization focally applied to the junction is followed by a brief period of very intense facilitation. This can be seen in the tetrodotoxin-treated preparation, e.g. by lengthening the depolarization from 1 to 2 msec which can cause a more than fifty-fold increase in transmitter release. This large ;early facilitation' (which presumably occurs also during the course of a normal action potential) is discussed in relation to the ;calcium hypothesis'.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1968.sp008469

The role of calcium in neuromuscular facilitation

According to present knowledge, the process of neuromuscular transmission can be described by the following scheme: nerve impulse -+ acetylcholine -end-plate potential -* muscle impulse -* contraction. The evidence for this chain has been summarized by Eccles (1948), Hunt & Kuffler (1950) and Rosenblueth (1950), whose reviews may be consulted for further references. While there is little doubt that acetylcholine is released by the nerve impulse and depolarizes the end-plate, the mechanism of these two actions is at present unknown and requires further investigation. The most immediate electrical sign of neuromuscular transmission is the end-plate potential, a local depolarization of the muscle fibre which is presumably due to the direct action of the neuromuscular transmitter. By measuring this electrical change under suitable conditions, some light can be thrown on the preceding steps of the transmission process. The object of this paper is to investigate the properties ofthe end-plate potential even more closely than has previously been attempted, making use of the method of intra-cellular recording which has been developed by Graham & Gerard (1946), Ling & Gerard (1949) and Nastuk & Hodgkin (1950). This method offers several advantages: resting and action potentials at individual junctions can be recorded in whole muscles, without microdisection or even removing the muscle from a Ringer bath, and the measurements do not suffer from uncertainties which are usually associated with the shunting effect of the interstitial fluid. The immediate concern of the present work is to determine the electric charge which passes through the end-plate membrane during the transmission of one impulse and to throw some light on the mechanism by which the transfer of ions across the end-plate is brought about.

Bernard Katz

Papers

Quantal components of the end-plate potential

Spontaneous subthreshold activity at motor nerve endings

The role of calcium in neuromuscular facilitation

An analysis of the end‐plate potential recorded with an intra‐cellular electrode

The release of neural transmitter substances