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Competing accounts propose that working memory (WM) is subserved either by persistent activity in single neurons, or by time-varying activity across a neural population, or by activity-silent mechanisms carried out by hidden internal states of the neural population. While WM is traditionally regarded to originate exclusively from neuronal interactions, cortical networks also include astrocytes that can modulate neural activity. We propose that different mechanisms of WM can be brought forth by astrocyte-mediated modulations of synaptic transmitter release. In this account, the emergence of different mechanisms depends on the network’s spontaneous activity and the geometry of the connections between synapses and astrocytes.

Spiking neural networks (SNNs) receive widespread attention because of their low-power hardware characteristic and brain-like signal response mechanism, but currently, the performance of SNNs is still behind Artificial Neural Networks (ANNs). We build an information theory-inspired system called Stochastic Probability Adjustment (SPA) system to reduce this gap. The SPA maps the synapses and neurons of SNNs into a probability space where a neuron and all connected pre-synapses are represented by a cluster. The movement of synaptic transmitter between different clusters is modeled as a Brownian-like stochastic process in which the transmitter distribution is adaptive at different firing phases. We experimented with a wide range of existing unsupervised SNN architectures and achieved consistent performance improvements. The improvements in classification accuracy have reached 1.99% and 6.29% on the MNIST and EMNIST datasets respectively., Comment: Published at the 25th International Conference on Pattern Recognition (ICPR2020)

Brain function depends on a crucial feature: The ability of individual neurons to share packets of information, known as quantal transmission. Given the sheer number of tasks the brain has to deal with, this information sharing must be extremely rapid. Synapses are specialized points of contact between neurons, where fast transmission takes place. Though the basic elements and functions of the synapse had been established since the 1950s, the molecular basis for regulation of fast synaptic transmitter release was not known 20 years ago. However, around 1990, crucial discoveries were made by Richard Scheller, James Rothman, and Thomas Sudhof, leading a few years later to the formulation of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) hypothesis and a new understanding of the molecular events controlling vesicular release of transmitter in synapses. The 2010 Kavli Prize in neuroscience was awarded to these three researchers, “for their work to reveal the precise molecular basis of the transfer of signals between nerve cells in the brain.”

Unlike most other secretory processes, neurotransmitter release at chemical synapses is extremely fast, tightly regulated, spatially restricted, and dynamically adjustable at the same time. In this review, we focus on recent discoveries of molecular and cell biological processes that determine how fusion competence of vesicles is achieved and controlled in order to suit the specific requirements of synaptic transmitter release with respect to speed and spatial selectivity.

Understanding the principles of brain work is impossible without understanding the functioning of its main elements, such as synaptic contacts between neurons. The history of the study of mechanisms responsible for the information processing and transmission in the synapses is already several decades long; therefore, a number of methods and lines of research “classical” for this field have been elaborated. One of these lines is investigation of the properties of synaptic transmitter quantal release, and one of standard methods for the estimation of quantal release content (the average number of quanta released during one transmission act) is the estimation of the inverse squared coefficient of variation of the evoked postsynaptic response amplitude ( CV –2 ). Here, we describe the type of synapses for which a change in CV –2 is not necessarily accompanied by a change in quantal content, set the question as to the cause of this phenomenon, and offer an explanation for this problem, illustrating it with a computer model.

After an overview of the early, chequered history of the discovery of GABA and its gradual acceptance as inhibitory synaptic transmitter in the brain, the article lists and discusses some of the more unexpected later developments in studies of GABA, especially its role as excitatory transmitter in the immature brain.

The high concentration in brain of unbound l-glutamic acid (in its anionic form, l-glutamate) fuelled considerable speculation as to its role in central nervous function more than 50 years ago. Claims in the 1940s that it could improve cognitive acuity in patients with mental impairment were particularly intriguing, though later refuted. In the early 1950s Hayashi [(1954) Keio J. Med. 3, 183–192] found that l-glutamate could cause convulsions and proposed that it might be a central synaptic transmitter. Soon thereafter, Curtis and colleagues [Curtis, Phillis and Watkins (1959) Nature (London) 183, 611] showed that l-glutamate depolarized and excited central neurons, as expected for an excitatory transmitter; however, various aspects of the action of l-glutamate seemed to argue strongly against a transmitter function. This negative view prevailed for some 20 years, before compelling evidence for such a role was adduced. Over the last two decades, extensive research has revealed a host of glutamate receptor subtypes, subserving several different functions in excitatory synaptic transmission. This paper gives a very brief and personal overview of the development of the field over the last 50 years from a mainly pharmacological standpoint.

The release of synaptic transmitter in chemical synapses is brought about by Ca2+ influx through voltage-dependent Ca2+ channels opened by depolarisation of presynaptic terminals. However, in some preparations transmitter release persists or increases in low-Ca2+ media, and it has therefore been proposed that transmitter release could also occur through a Ca2+-independent, carrier mediated process. In particular it has been suggested that this may be the case for synaptic transmission between photoreceptors and second order neurones of the vertebrate retina. From our recent experiments on synaptic transmission from photoreceptors to horizontal cells of turtle and salamander retinas, it appears that lowering extracellular Ca2+ can actually promote Ca2+ influx through voltage-activated Ca2+ channels via a modification of surface potential of plasma membranes. On the basis of this apparently paradoxical effect of low Ca2+ media, it is possible to reaccommodate the so-called Ca2+-independent release within the framework of Ca2+-dependent synaptic transmission without invoking unconventional mechanisms.

G.F. Gebhart, R.F. Schmidt (eds.), Encyclopedia of Pain, DO # Springer-Verlag Berlin Heidelberg 2013 receptors, which inhibit neuronal excitability through activation of K (potassium) channels and synaptic transmitter release through inhibition of presynaptic Ca channels. In most parts of the brain, GABA is the only fast inhibitory neurotransmitter, while GABA and glycine act in concert in the spinal cord, the brain stem, and selected areas of the brain, such as the cerebellum.

Neurons often receive massive concurrent bombardment of synaptic inhibition and excitation during functional network activity. This increases membrane conductance and causes fluctuations in membrane potential (V(m)) and spike timing. The conductance increase is commonly attributed to synaptic conductance, but also includes the intrinsic conductances recruited during network activity. These two sources of conductance have contrasting dynamic properties at sub-threshold membrane potentials. Synaptic transmitter gated conductance changes abruptly and briefly with each presynaptic action potential. If the spikes arrive at random times the changes in synaptic conductance are therefore stochastic and rapid during intense network activity. In comparison, sub-threshold intrinsic conductances vary smoothly in time. In the present study this discrepancy is investigated using two conductance-based models: a (1) compartment model and a (2) compartment with realistic slow intrinsic conductances. We examine the effects of varying the relative contributions of non-fluctuating intrinsic conductance with fluctuating concurrent inhibitory and excitatory synaptic conductance. For given levels of correlation in the synaptic input we find that the magnitude of the membrane fluctuations uniquely determines the relative contribution of synaptic and intrinsic conductance. We also quantify how V(m)-fluctuations vary with synaptic correlations for fixed ratios of synaptic and intrinsic conductance. Interestingly, the levels of V(m) -fluctuations and conductance observed experimentally during functional network activity leave little room for intrinsic conductance to contribute. Even without intrinsic conductances the variance in V(m) -fluctuations can only be explained by a high degree of correlated firing among presynaptic neurons.

We describe a model of synaptic transmitter release and presynaptic facilitation that is based on activation of release sites by single Ca2+ C microdomains. Facilitation is due to Ca2+ that remains bound to release sites between impulses. This model is inherently stochastic, but deterministic equations can be derived for the mean release. The number of equations required to describe the mean release is small, so it is practical to use the model with models of neuronal electrical activity to investigate the effects of different input spike patterns on presynaptic facilitation. We use it in conjunction with a model of dopamine-secreting neurons of the basal ganglia to demonstrate that transmitter release is greater when the neuron bursts than when it spikes continuously, due to the greater facilitation generated by the bursting impulse pattern. Finally, a minimal form of the model is described that is coupled to simple models of postsynaptic receptors and passive membrane to compute the postsynaptic voltage response to a train of presynaptic stimuli. This form of the model is appropriate for neural network simulations.

The relationship between calcium current and transmitter release was studied in squid giant synapse. It was found that the voltage-dependent calcium current triggers the release of synaptic transmitter in direct proportion to its magnitude and duration. Transmitter release occurs with a delay of approximately 200 mus after the influx of calcium. A model is presented which describes these relations formally.

IT is now generally accepted that GABA is an important inhibitory synaptic transmitter in the vertebrate central nervous system. However, there remain many problems in elucidating the precise roles of GABA in the brain. One important problem is the existence of a glial pool of GABA which makes it difficult to determine the origin of GABA released during experiments designed to demonstrate the release of GABA after nervous stimulation. It was thought at one time that this problem might be overcome by utilising the uptake processes for GABA to label the neuronal GABA pools, with for example, 3H-GABA. However, it is now clear that in many areas of the brain, GABA is also taken up by glial cells and in some areas, this glial uptake may actually predominate. The transport processes for GABA in neurones and glia have remarkably similar properties but do appear to have slightly different structural requirements.

Publisher Summary This chapter elaborates the importance of norepinephrine as a central synaptic transmitter. The ultimate test of the function of central noradrenergic synapses must result from the selective activation of these terminals and from the detection of their activity patterns in the unrestrained experimental animal. Excitatory responses to NE in the cerebral cortex were found to be more frequent when the animal was unanesthetised or under the influence of halothane anesthesia, while inhibitory cortical responses were more frequent with barbiturate anesthesia. Similarly, the pH of the NE solution to be iontophoretically applied also takes on critical importance, as pH values less than 4 are associated with major increases in the frequency of excitatory NE responses. The NE-containing pathway has not been amenable to selective electrical activation for comparisons of qualitative and pharmacological results on the specified postsynaptic population of test neurons. It is found that synaptic effects which were subjectible to selective activation were neither exclusively NE-containing nor sensitive to NE antagonists.

There are a number of discrete electro-physiological responses which can be recorded from the ventral horn. Those which can be related to anatomically defined structures, or at least to positions within the laminae of Rexed, include the responses of α-motoneurons, γ-motoneurons, α-motor axons, Renshaw cells, type A interneurons, and commissural neurons. Recurrent inhibition is best explained by the excitation of Renshaw cells by recurrent collaterals of motor axons; Renshaw cells in turn inhibit motoneurons. The synaptic transmitter released by the recurrent collaterals is acetylcholine. That released by Renshaw cells may be glycine or a related substance. Recurrent facilitation is best explained by the inhibition by Renshaw cells of inhibitory interneurons. Candidate inhibitory interneurons include type A interneurons, which may mediate group I reciprocal inhibition, and other Renshaw cells. There is no good reason to believe that Renshaw cells are actually the terminals of recurrent collaterals or the dendrites of motoneurons rather than interneurons. However, there is also no convincing evidence that Renshaw cells are necessarily short-axoned cells.

1. Each giant serotonin cell in Helix pomatia makes synaptic connexions with three non-amine-containing neurones: the anterior, middle and posterior buccal cells. 2. Individual e.p.s.p.s, of 500-600 msec duration, were observed in both left and right middle cells following each evoked giant serotonin cell action potential. They were facilitated with repetitive stimulation of the giant serotonin cells and summed to give rise to an action potential. The membrane resistance of the middle cells was reduced when the giant serotonin cells were stimulated to fire rapidly. Evidence is presented which suggests that the link between each giant serotonin cell and each middle cell is monosynaptic. 3. Iontophoretically applied serotonin produced a depolarizing potential change in the middle cell perikaryon; the response rapidly desensitized on repetitive application. 4. Morphine abolished reversibly the middle cell serotonin potential and antagonized transmission from the giant serotonin cells to the middle cells. Lowering the Na concentration of the medium reversibly diminished the size of the serotonin potential and the giant serotonin cell elicited e.p.s.p.s in the middle cells. 5. Reserpine, which depletes serotonin in the giant serotonin cell, impaired transmission from these cells to the middle cells. 6. The results suggest that serotonin is the synaptic transmitter released from the giant serotonin cells on to the middle cells and that this system is a suitable model for further analysis of the neuronal role of serotonin.

Succinic semialdehyde dehydrogenase is the final enzyme in the degradative pathway of γ-aminobutyric acid, a postulated inhibitory synaptic transmitter. This study reports a specific, sensitive technique for the localization of succinic semialdehyde dehydrogenase in rat brain. The technique utilizes the direct reduction of nitroblue tetrazolium by reduced pyridine nucleotide at an alkaline pH, a mechanism of formazan production substantiated by biochemical studies. The succinic semialdehyde dehydrogenase histochemical reaction is completely inhibited by p-hydroxybenzaldehyde and m-hydroxybenzaldehyde, compounds which have no effect on succinic acid dehydrogenase and reduced diphosphopyridine nucleotide diaphorase. Conversely, succinic acid dehydrogenase and reduced diphosphopyridine nucleotide diaphorase are inhibited by malonate and nordihydroguaiaretic acid, respectively, substances which have no effect on succinic semialdehyde dehydrogenase. The distribution and intensity of staining for succinic semialdehyde dehydrogenase are different from that seen following the succinic acid dehydrogenase and reduced diphosphopyridine nucleotide diaphorase reactions and can be localized to groups of neurons and their cell processes, e.g., the Purkinje cell dendritic tree, and in specific regions of neuropil.

There are a number of discrete electro-physiological responses which can be recorded from the ventral horn. Those which can be related to anatomically defined structures, or at least to positions within the laminae of Rexed, include the responses of α-motoneurons, γ-motoneurons, α-motor axons, Renshaw cells, type A interneurons, and commissural neurons. Recurrent inhibition is best explained by the excitation of Renshaw cells by recurrent collaterals of motor axons; Renshaw cells in turn inhibit motoneurons. The synaptic transmitter released by the recurrent collaterals is acetylcholine. That released by Renshaw cells may be glycine or a related substance. Recurrent facilitation is best explained by the inhibition by Renshaw cells of inhibitory interneurons. Candidate inhibitory interneurons include type A interneurons, which may mediate group I reciprocal inhibition, and other Renshaw cells. There is no good reason to believe that Renshaw cells are actually the terminals of recurrent collaterals or the dendrites of motoneurons rather than interneurons. However, there is also no convincing evidence that Renshaw cells are necessarily short-axoned cells.

DENERVATION of the limb of a lower vertebrate is followed by an ordered reinnervation, so that the normal pattern of muscle use is restored1. Higher vertebrates, however, seem to be much less selective in their reinnervation2. There is no absolute restriction on inappropriate reinnervation in lower vertebrates3; the return of normal function is due, at least in part, to multiple reinnervation of muscle fibres by different nerves, followed by a repression of function of less appropriate contacts4. Yip and Dennis5 have shown that the repression of function in inappropriate nerve-muscle junctions in the newt, Notopthalmus viridescens, involves a reduction in the number of quanta of synaptic transmitter released by each nerve impulse. If the initiating event in this process is reduction or loss of the ability of inappropriate nerve terminals to release transmitter6,7, there should be evidence of the continued presence of these terminals even after transmission from the inappropriate nerve has been repressed. In this paper we present such evidence as a result of our studies in the axolotl.

Microiontophoretic application of GABA and its antagonist, picrotoxin, altered focal potentials evoked in the caudate nucleus by stimulation near the recording site to a much greater extent than potentials elicited by stimulation of afferent pathways, suggesting that GABA is a transmitter of interneurons in this nucleus.

Acetylcholine (ACh) has been considered a possible central synaptic transmitter for some 50 years (Dale, 1938). What kind of role cholinergic synapses might play in brain function is a topic that has long fascinated Alexander Karczmar (e. g. Karczmar, 1969; 1973). It is therefore entirely appropriate to review here briefly what we know about cholinergic action in the cerebral cortex.

The hypothesis that a synaptic transmitter is released by photoreceptors in the dark is supported by experiments in which cobalt was used as a synaptic blocking agent, while intracellular recordings of receptors and neurons that are directly postsynaptic to receptors were maintained. In the dark the depolarizing bipolars are hyperpolarized, whereas the hyperpolarizing bipolars are depolarized.

The numerous pharmacological studies of GABA in brain described in the literature have been carried out mainly with the purpose of investigating the possible role of this amino acid as an inhibitory synaptic transmitter in the CNS. The experimental approaches used have been essentially the following: (1) modifying the metabolism of GABA in the living animal by systemic, intracranial, or topical application of compounds and attempting to correlate the biochemical effects with a behavioral or electroencephalographic parameter, (2) applying substances to individual neurons by means of microiontophoresis and studying their effect on the inhibitory action of GABA also applied iontophoretically on the same neuron, (3) adding drugs to media containing slices, homogenates, or subcellular particles of nervous tissue and measuring their effect on the uptake and the release of GABA by these preparations, or (4) combinations of the former three approaches.

Acetylcholine (ACh) is probably a synaptic transmitter substance in the retina of most, if not all, vertebrates (17,35). However, in spite of a wealth of biochemical (3,22,37,44,45), pharmacological (16,25,38,43,49,50) and histochemical (4,27,39,46) evidence which supports a transmitter role for ACh in the retina, there has only been one demonstration of ACh release in response to flashes of light (26).

AN adequate model for the nature of the memory trace at the neuronal level should provide for a sequence of physiological mechanisms which would include ‘read-in’ of the neuronal change, ‘storage’ processes that impart an enduring quality, and ‘read-out’ of the change in the form of an altered neuronal response to an appropriate neural input. The framework for such a neuronal model seems to be provided by the features of a novel heterosynaptic interaction in a mammalian sympathetic ganglion. It had been found previously that one synaptic transmitter (the catecholamine dopamine, DA) could produce a specific and enduring enhancement, lasting for at least several hours, of the subsequent responses to another synaptic transmitter (acetylcholine, ACh)1. We have now found that the retention of this DA-induced change can be disrupted by cyclic GMP in a strikingly time-dependent manner that is similar, in principle, to the well known disruptability feature of the memory storage process2,3. Additional evidence indicates that the production and storage of the enduring change initiated by DA are mediated intraneuronally by cyclic AMP. We present here a scheme which outlines the cellular pathways postulated to carry out the sequence of events from ‘read-in’ through to ‘read-out’.

1. The effects of ACh, D-tubocuraine and atropine on the electrical activity of the ampullae of Lorenzini of the skate were studied. 2. ACh (10(-5)M) caused an increase in frequency of afferent discharges in all receptors under study. 3. When excitability was abolished by high Mg2+ solution (50 mM) perfusion with 50 mM Mg2+ plus ACh did not induce firing in the afferent fibres. 4. Cholinergic antagonists (D-tub and atr) did not block the synaptic transmission. 5. The results suggest that ACh is unlikely to be the synaptic transmitter in the ampullae of Lorenzini.

Previous studies with probabilistic neural nets in which the neural connections are set up by means of chemical markers, revealed the existence of multiple memory domains. We generalized these studies by considering the intrinsic noise of the systems, caused by the spontaneous release of synaptic transmitter substance. A simple mathematical model is developed, which yields characteristics of multiple memory domains analogous to those occurring in noiseless nets.

Although it has been known for more than 30 years that Ca ions trigger the release of neurotransmitters at chemical synapses (Katz, 1969), the molecular basis for this important physiological event is unclear. While biochemical and theoretical studies have proposed a number of models to account for this presynaptic triggering action of Ca, none has emerged as a consensus favorite (Augustine, Charlton and Smith, 1987). This problem arises, in part, because there have been few attempts to test or evaluate these hypotheses.

Compound fiber action potentials of stratum radiatum afferents in slices from human and rat hippocampus are shown to be prolonged by 4-aminopyridine (4-AP). This action can explain the enormous increase in synaptic transmitter release caused by 4-AP.

Until recently, no mechanism has been offered to account simultaneously for phasic release of transmitter and its facilitation at the frog neuromuscular junction. Katz & Miledi (1) showed that external calcium was necessary at the time of the first nerve impulse and suggested that calcium entered the terminal and, by binding to some receptor site at the presynaptic terminal, released transmitter. The “residual calcium” hypothesis for facilitation evolved from their suggestion (2) that a residuum of “active calcium” remains within the terminal following an action potential for several milliseconds and is able to enhance the amount of transmitter released by succeeding stimuli.

GABA which is now generally believed to be an important inhibitory synaptic transmitter substance in the vertebrate central nervous system (see Krnjevic 1974) is thought to be inactivated after its release from nerve terminals by uptake processes which are present in some neurones and glia (see Iversen & Kelly, 1975). These transport processes for GABA in neurones and glia have very similar properties but can be distinguished by their structural requirements (Bowery et al, 1976). We have found that a conformationally-restricted analogue of GABA, cis 3-aminocyclohexane carboxylic acid (ACHC), which has previously been reported to competitively inhibit GABA transport in slices of cerebral cortex (Beart et al, 1972), is a relatively selective inhibitor of neuronal GABA transport (Bowery et al, 1 976). Studies with radiolabeled ACHC (3H-ACHC) indicate that the analogue is a selective substrate for the neuronal GABA transport process.

There is now considerable evidence for the involvement of y-aminobutyric acid (GABA) as an inhibitory (Curtis and Felix, 1971; Curtis, Duggan, Felix, Johnston and McLennan, 1971; Krnjevie and Schwartz, 1967; Straughan, Neal, Simmonds, Collins and Hill, 1971) and possibly excitatory (Davidoff, 1972; DeGroat, 1969; Shank, Pong, Freeman and Graham, 1974) transmitter in many areas of the vertebrate central nervous system (CNS). In the past few years we have strengthened the GABA hypothesis in the supraspinal areas of the mammalian vestibular and oculomotor system because they offer the unique opportunity to study identified physiological pathways by both intracellular and extracellular recordings (Ito, Highstein and Tsuchiya, 1970; Baker, Mano and Shimazu, 1969; Precht, Baker and Okada, 1973a; Precht, Schwindt and Baker, 1973b). This paper will review and present new evidence on the use of pharmacological agents to elucidate the nature of the inhibitory synaptic transmitter (s) in the ocular and vestibular nuclei.

Among the neurochemicals considered to be candidates for synaptic transmitter function within the central nervous system, the conceptual link to psychopharmacological actions has been particularly strong for norepinephrine (NE). Basic research in psychiatry has concentrated on the changes in brain monoamine metabolism produced by psychoactive drugs (see Snyder, 1974) to develop catecholamine theories of mental diseases. In such a psychopharmacological model, NE is presumed to be a central synaptic transmitter, but the actual functional controls (i.e., excitation or inhibition) exerted by such synapses, their exact cellular location, and their mechanism of action have not been known. This chapter will focus on the methods by which the central receptors for NE may be characterized as to location, function, and pharmacological significance.

Like Herbert Jasper, whom I have had the privilege of knowing as a stimulating colleague and friend for more than 35 years, I have approached the issue of brain function along more than one experimental strategy. One involved direct studies of human cerebral processes in relation to conscious, subjective experience (e.g., Libet, 1973, 1982, 1985a). The other has been at the synaptic transmitter level, as it relates to slow functions of the brain. This stemmed from early work with Ralph Gerard on slow or “steady” potentials in brain (e.g., Gerard and Libet, 1940; Libet and Gerard, 1941) in which we had discovered modes of cerebral neuronal interaction that seemed to require mechanisms different from those available in fast axonal and synaptic transmissions. That expectation attracted me to investigate the slow potentials observed by Rose Eccles in sympathetic ganglia (Eccles, 1952), and that led to discoveries and analyses of a whole new class of slow synaptic mechanisms by myself and then many others. The characteristics of these slow synaptic actions greatly expanded the availability of processes that could help to mediate the slower and many of the higher functions of the brain (e.g., Libet, 1978, 1986).

When applied by microiontophoresis, substance P (sP) had a strong, but slow and prolonged excitatory action on nearly half the neurones tested in the lumbar spinal cord of cats. Motoneuronal antidromic field potentials only occasionally showed a significant effect of sP. Cerebral cortical neurones in cats and rats were much less readily excited than spinal interneurones. Some unresponsive units showed evidence of a depressant effect of sP. Although sP may have a significant function in central afferent pathways, it is not likely to be a quickly-acting synaptic transmitter.

The synaptic transmitter function of 5-hydroxytryptamine (5-HT) has been discussed for many years. However, crucial evidence relating this indoleamine to the function of a specific synapse has not yet been obtained either in vertebrates or in invertebrates.