Efficiency Of Synaptic Transmission Research Articles

Alzheimer's Disease-Like Tau Neuropathology Leads to Memory Deficits and Loss of Functional Synapses in a Novel Mutated Tau Transgenic Mouse without Any Motor Deficits

Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation.

The Potential of Caffeine for Functional Modification from Cortical Synapses to Neuron Networks in the Brain

Structure and function of the brain are use-dependent variables based on "synapse plasticity". Since synapses are driven by chemical transmitters, synaptic functions are liable to be modified by extrinsic chemicals displaying affinities for synaptic receptors or modulators. Caffeine is a widely used chemical substance that can invade synapses, and has several biochemical and metabolic actions on synaptic activities. This review focuses on the actions of caffeine on changes in structure and function in the region of the hippocampal formation and neocortex, which exhibit high synapse plasticity. At the synapse level, various synaptic receptors and channel activities are modulated by caffeine via mobilization of intracellular calcium, inhibition of phosphodiesterase, antagonism of adenosine receptors and GABA receptors. These actions of caffeine enable neurons to induce plastic changes in the properties of synaptic activities, such as synaptic transmission efficiency and morphology. At the network level, caffeine has the ability to activate cortical neural oscillators that deliver repetitive N-methyl-D-aspartate receptor-dependent signals to surrounding areas, causing strengthening of long-range inter-cortical communications. Caffeine might thus allow reorganization of cortical network functions via synaptic mobilizations.

In Vivo Regulation of Acetylcholinesterase Insertion at the Neuromuscular Junction

The efficiency of synaptic transmission between nerve and muscle depends on the number and density of acetylcholinesterase molecules (AChE) at the neuromuscular junction. However, little is known about the way this density is maintained and regulated in vivo. By using time lapse and quantitative fluorescence imaging assays in living mice, we demonstrated that insertion of new AChEs occurs within hours of saturating pre-existing AChEs with fasciculin2, a snake toxin that selectively labels AChE. In the absence of muscle postsynaptic activity or evoked nerve presynaptic neurotransmitter release, AChE insertion was decreased significantly, whereas direct stimulation of the muscle completely restored AChE insertion to control levels. This activity-dependent AChE insertion is mediated by intracellular calcium. In muscle stimulated in the presence of a Ca2+ channel blocker or calcium-permeable Ca2+ chelator, AChE insertion into synapses was significantly decreased, whereas ryanodine or ionophore A12387 treatment of blocked and unstimulated synapses significantly increased AChE insertion. These results demonstrated that synaptic activity is critical for AChE insertion and indicated that a rise in intracellular calcium either through voltage-gated calcium channels or from intracellular stores is critical for proper AChE insertion into the adult synapse.

SNAP-29-mediated Modulation of Synaptic Transmission in CulturedHippocampalNeurons

Identifying the molecules that regulate both the recycling of synaptic vesicles and the SNARE components required for fusion is critical for elucidating the molecular mechanisms underlying synaptic plasticity. SNAP-29 was initially isolated as a syntaxin-binding and ubiquitously expressed protein. Previous studies have suggested that SNAP-29 inhibits SNARE complex disassembly, thereby reducing synaptic transmission in cultured superior cervical ganglion neurons in an activity-dependent manner. However, the role of SNAP-29 in regulating synaptic vesicle recycling and short-term plasticity in the central nervous system remains unclear. In the present study, we examined the effect of SNAP-29 on synaptic transmission in cultured hippocampal neurons by dual patch clamp whole-cell recording, FM dye imaging, and immunocytochemistry. Our results demonstrated that exogenous expression of SNAP-29 in presynaptic neurons significantly decreased the efficiency of synaptic transmission after repetitive firing within a few minutes under low and moderate frequency stimulations (0.1 and 1 Hz). In contrast, SNAP-29 did not affect the density of synapses and basal synaptic transmission. Whereas neurotransmitter release was unaffected during intensive stimulation, recovery after synaptic depression was impaired by SNAP-29. Furthermore, knockdown of SNAP-29 expression in neurons by small interfering RNA increased the efficiency of synaptic transmission during repetitive firing. These findings suggest that SNAP-29 acts as a negative modulator for neurotransmitter release, probably by slowing recycling of the SNARE-based fusion machinery and synaptic vesicle turnover.

Three-dimensional reconstruction of synapses and dendritic spines in the rat and ground squirrel hippocampus: New structural-functional paradigms for synaptic function

Published data are reviewed along with our own data on synaptic plasticity and rearrangements of synaptic organelles in the central nervous system. Contemporary laser scanning and confocal microscopy techniques are discussed, along with the use of serial ultrathin sections for in vivo and in vitro studies of dendritic spines, including those addressing relationships between morphological changes and the efficiency of synaptic transmission, especially in conditions of the long-term potentiation model. Different categories of dendritic spines and postsynaptic densities are analyzed, as are the roles of filopodia in originating spines. The role of serial ultrathin sections for unbiased quantitative stereological analysis and three-dimensional reconstruction is assessed. The authors' data on the formation of more than two synapses on single mushroom spines on neurons in hippocampal field CA1 are discussed. Analysis of these data provides evidence for new paradigms in both the organization and functioning of synapses.

Synaptogenèses et épigenèses cérébrales

Synaptic plasticity, or epigenesis, is present and varies throughout the whole life of the cerebral cortex. The adult synapse is formed of large and variable proteins assemblies acting as molecular switches leading to many distinct functional states. In the flow of activity circulating through the synaptic circuits, these multiple synaptic states transitions are modulated by the levels and sequences of activations of the pre- and post-synaptic domains. The efficiency of synaptic transmission is also modulated by competition and/or cooperativity with neighbouring synapses, and by many neuromodulations. Some transitions eventually lead to synaptogenesis. In the adult cerebral cortex, synaptogenesis remains a local event; axonal and dendritic arbors are not reshaped. On the contrary, during pre- and post-natal synaptogenesis, the same molecular mechanisms lead to a significant reorganization of the axonal and dendritic arbors. Early in the development, synapses are generated and differentiate under the control of robust mechanisms governed by genes. Then, during the critical periods, extending from the end of gestation to the end of puberty, the refinement of the synaptic architecture becomes experience-expectant. This "epigenetic opening" of synaptogenesis to environment is maximal in the human brain. It is the source of the exceptional cognitive adaptability of our species, and possibly one of its major fragility. Epigenetic manipulations of these critical periods are undertaken, allowing restoration of synaptic plasticity also in the adult brain.

The Kinetic Profile of Intracellular Calcium Predicts Long-Term Potentiation and Long-Term Depression

Efficiency of synaptic transmission within the neocortex is regulated throughout life by experience and activity. Periods of correlated or uncorrelated presynaptic and postsynaptic activity lead to enduring changes in synaptic efficiency [long-term potentiation (LTP) and long-term depression (LTD), respectively]. The initial plasticity triggering event is thought to be a precipitous rise in postsynaptic intracellular calcium, with higher levels inducing LTP and more moderate levels inducing LTD. We used a pairing protocol in visual cortical brain slices from young guinea pigs with whole-cell recording and calcium imaging to compare the kinetic profiles of calcium signals generated in response to individual pairings along with the cumulative calcium wave and plasticity outcome. The identical pairing protocol applied to layer 2/3 pyramidal neurons results in different plasticity outcomes between cells. These differences are not attributable to variations in the conditioning protocol, cellular properties, inter-animal variability, animal age, differences in spike timing between the synaptic response and spikes, washout of plasticity factors, recruitment of inhibition, or activation of different afferents. The different plasticity outcomes are reliably predicted by individual intracellular calcium transients in the dendrites after the first few pairings. In addition to the differences in the individual calcium transients, the cumulative calcium wave that spreads to the soma also has a different profile for cells that undergo LTP versus LTD. We conclude that there are biological differences between like-type cells in the dendritic calcium signals generated by coincident synaptic input and spiking that determine the sign of the plasticity response after brief associations.

Enhancement of Information Transmission Efficiency by Synaptic Failures

Many synapses have a high percentage of synaptic transmission failures. I consider the hypothesis that synaptic failures can increase the efficiency of information transmission across the synapse. I use the information transmitted per vesicle release about the presynaptic spike train as a measure of synaptic transmission efficiency and show that this measure can increase with the synaptic failure probability. I analytically calculate the Shannon mutual information transmitted across two model synapses with probabilistic transmission: one with a constant probability of vesicle release and one with vesicle release probabilities governed by the dynamics of synaptic depression. For inputs generated by a non-Poisson process with positive autocorrelations, both synapses can transmit more information per vesicle release than a synapse with perfect transmission, although the information increases are greater for the depressing synapse than for a constant-probability synapse with the same average transmission probability. The enhanced performance of the depressing synapse over the constant-release-probability synapse primarily reflects a decrease in noise entropy rather than an increase in the total transmission entropy. This indicates a limitation of analysis methods, such as decorrelation, that consider only the total response entropy. My results suggest that synaptic transmission failures governed by appropriately tuned synaptic dynamics can increase the information-carrying efficiency of a synapse.

Synaptic transmission correlates of general mental ability

Nerve conduction velocity (NCV) and efficiency of synaptic transmission are two possible biological mechanisms that may underpin intelligence. Direct assessments of NCV, without synaptic transmission, show few substantial or reliable correlations with cognitive abilities [Intelligence 16 (1992) 273]. We therefore assessed the latencies of reflexes involving one and many synapses to determine whether variations in speed of synaptic conduction are related to cognitive abilities and reaction times (RTs). NCV was estimated by measuring speed of nerve conduction in the patellar reflex arc and speed of finger withdrawal following electric shock. Speed and efficiency of neural transmission were indirectly measured via simple and choice RT tasks. Several hypothesized relationships were supported; however, the results tend to be inconsistent. The theoretical implications of the findings are discussed.

Muscarinic receptors in airways diseases

It was with some trepidation that I undertook the task of reviewing this book. After all what new could be said about the use of agents which have their origin before recorded time and are almost certainly the oldest drugs to be used in respiratory medicine. In fact, this book is an absolute delight and kept me entertained and stimulated throughout what would have been a very tedious flight. The key to understanding the book's success is in the title of the series rather than the volume. Muscarinic Receptors in Airways Disease is published in the Progress and Inflammation Research Series. The volume does not contain a detailed exposition of the effect of the cholinergic nervous system in bronchoconstriction but rather concentrates on other aspects of muscarinic responses, particularly as one might expect in the field of inflammation. The editors have gathered together a distinguished group of authors who are quite clearly giving of their best in each chapter. The volume starts with a super exposition of the parasympathetic mechanisms by Unden & Myers. In this and virtually every other chapter there was an important concept which was new (at least to me). I had not realized that the efficiency of synaptic transmission varies between different junctions. The so called axo-dendritic synapse or the axo-somatic synapses differ greatly in their efficiency of transmission and because of the relatively low efficiency of airways ganglia there is very great opportunity for modulation of synaptic transmission by external forces, either neuronal or inflammatory. In the next chapter Wessler & Kirkpatrick introduced me to non-neuronal acetylcholine in the airways, a concept that I had not thought about deeply but it is expounded with great lucidity. This chapter along with virtually every other is extensively referenced with nearly 200 citations. The next four chapters deal with the muscarinic receptors, their localization and regulation. Refreshingly the non-constricting M2 receptor is highlighted and I came away thinking that this was an important target potential for new drugs. Peter Barnes does his usual lucid instruction on the gene regulation of muscarinic receptors. The final part of the book on the clinical pharmacology I found to be the weakest, perhaps because of the previous very high standard of writing. Having said that, Kenneth Chapman is given the thankless task of reviewing previous anticholinergic therapy in asthma and COPD and responds with a superb opening few pages on the long and fascinating history of anticholinergic therapy. The final chapter on a novel perspective of anticholinergic therapy I found disappointing and not entirely up to date. This is particularly a shame since Bernd Disse could have given us greater insight on what could be a very exciting drug, tiotropium. Overall I would highly recommend this volume. It is a must for anyone interested in the nervous control of the airways and I am sure I will be referring to it again and again. It has made me go back and look at the study on which the M2 regulation of neurogenic bronchoconstriction is based. The entire edifice is built on the response of seven normal volunteers! Finally, I was saddened but not surprised to see that in a book of 260 pages the commonest respiratory symptom, which is almost entirely neurogenic, was mentioned only in passing, yet cough accounts for more consultations than any other respiratory disease put together.

Expression and plasticity of glutamate receptors in the supraoptic nucleus of the hypothalamus.

Magnocellular neuroendocrine cells (MNCs) of the supraoptic nucleus of the hypothalamus (SON) produce and release the hormones vasopressin (VP) and oxytocin (OT) in response to a variety of stimuli to regulate body water and salt, parturition and lactation. Hormone release is influenced by the pattern of neuronal firing of these MNCs, which, in turn, is governed by intrinsic conductances and synaptic inputs, including those mediated by the neurotransmitter glutamate. Functional and molecular evidence has confirmed the expression of AMPA-, NMDA-, and metabotropic-type glutamate receptors in the SON, that together may orchestrate the effects of glutamatergic transmission on neuroendocrine function. However, the specific roles of the different subtypes of glutamate receptors is not yet clear. As with other central neurons, the subunit composition of glutamate receptors on MNCs will likely determine their properties and may potentially help define the differential properties of VP- and OT-producing MNCs. Possible functions of glutamate receptors on SON MNCs include altering excitatory synaptic transmission of osmotic information, neuronal firing, hormone production and release, and calcium signaling. Of interest are the anatomical, molecular, and functional changes at glutamatergic synapses in the SON that occur in response to pertinent physiological stimuli or development. These types of plasticity may include changes in glutamatergic synaptic density, glutamate receptor levels, or glutamate receptor subunit expression, all of which can affect the efficiency of synaptic transmission.

Responses of hippocampal neurons at different stages of acquisition of conditioned reflex avoidance in rats.

The electrophysiological properties of hippocampal slices from trained and untrained rats presented with identical numbers of combinations during acquisition of a conditioned two-sided avoidance reaction were compared. Associative learning (presentation of combinations of conditioned and unconditioned stimuli) was accompanied by gradual increases in the amplitude of the population spike in hippocampal field CA1. However, achievement of the learning criterion was accompanied by a decrease in the amplitude of the population spike. The same type of difference between groups was seen in field CA1 using low-intensity stimulation of Schaffer collaterals, while there was no change in the amplitude at maximum-intensity stimulation. After the rats achieved the learning criterion, the level of facilitation in conditions of paired stimuli was significantly greater than in untrained animals and also as compared with the passive and active controls. These data provide evidence supporting the hypothesis that changes in the efficiency of synaptic transmission occur during the learning process. However, the direction of changes depends on the extent of training.

Dendritic receptors made to order

A fundamental property of many synapses in the brain is an ability to modulate their efficacy of transmission in response to incoming signals. Such changes to the efficiency of synaptic transmission could underlie many neuronal processes, including learning and memory. It has been shown that modification of the density and/or subunit composition of neurotransmitter receptors in the postsynaptic (dendritic) membrane is one mechanism by which neurons can modify their synaptic strength. The synthesis and targeting of such receptor proteins to dendritic areas was thought to be exclusively as a result of production of the proteins within the cell body followed by packaging, sorting and timely transportation to the dendritic membrane. However, the findings of Kacharmina et al. 1xStimulation of glutamate receptor protein synthesis and membrane insertion within isolated neuronal dendrites. Kacharmina, J.E. et al. Proc. Natl. Acad. Sci. USA. 2000; 97: 11545–11550Crossref | PubMedSee all References show that, not only can neurotransmitter receptors be synthesized inside the dendrites and inserted into the membrane, but that this process is pharmacologically sensitive.The production of a transmembrane protein was thought to necessitate the complete machinery of cellular protein synthesis, as found in the cell body. Although parts of this machinery have been identified in dendrites, and protein synthesis is known to occur there, the presence of everything needed for membrane protein synthesis in dendrites was controversial. Kacharmina et al. addressed this problem by expressing neurotransmitter receptors in mechanically isolated dentrites. Rat hippocampal neurons were cultured on coverslips and their dendrites were severed using a microelectrode. The remaining cell body was removed by aspiration to leave an intact set of dendrites on the coverslip. The investigators then liposomally transfected mRNA encoding either an N- or C-terminal cMyc-tagged glutamate receptor (GluR2) into the dendrites and showed that this receptor was successfully synthesized in the severed dendrites. The N-terminus of AMPA glutamate receptors is known to be extracellular, thus demonstration that the cMyc epitope of the N-terminally tagged GluR2 is externally located would show that the protein was integrated into the dendritic membrane which is a prerequisite for functionality in this class of receptors. The investigators achieved this by immunolabeling the N-terminal GluR2 cMyc epitope on transfected dendrites without permeabilizing the plasma membrane, indicating that the N-terminus of the GluR2 is translocated to the extracellular milieu. Finally, the investigators showed that dendritic GluR2 synthesis could be stimulated by DHPG, a metabotropic glutamate receptor agonist. In the absence of DHPG, GluR2 expression in the transfected dendrites was low to negligible, however DHPG application dramatically increased receptor expression in the severed dendrites.The results presented in this paper show that neuronal dendrites have the capacity to autonomously direct transmembrane receptor synthesis in response to external stimuli. Whether this synthesis is via a conventional ER-Golgi-sorting pathway that is self-contained in the dendrite, or via a novel mechanism is unknown. However, the finding that individual dendrites can locally synthesize neurotransmitter receptors has significant implications for our understanding of many neuronal processes. This mechanism could explain how individual synapses are selectively strengthened, by modification of their ‘receptor repertoire’ in response to the activity of their specific pre-synaptic input. A few questions remain to be answered, such as whether dendritic membrane protein synthesis occurs in vivo, and if the dendritically synthesized receptors are indeed functional. However, these findings certainly add another arrow to the quiver of mechanisms that may underlie memory processes in the brain.

Changes of Properties of Glutamatergic Synapses in the Hippocampus of Rats with Behavioral Depression and Modeling of the Changes in vitro

Stress-induced (72-h-long social isolation-evoked) behavioral depression in rats was shown to be accompanied by a significant moderation of long-term potentiation (LTP) and a concurrent intensification of long-term depression (LTD) and depotentiation of synaptic transmission in the hippocampal CA1 region. Such changes of the properties of glutamatergic synapses in the hippocampus can be modeled by 1-h-long application of a synthetic glucocorticoid (GC), prednisolone (1 μM), to hippocampal slices from intact rats. In this case, two-phase changes in the efficiency of synaptic transmission in the CA1 are observed: depression is followed by short facilitation. Prednisolone-determined changes in synaptic transmission in the CA1 region are of a presynaptic nature. Facilitation of prednisolone-evoked transmission could be reproduced by application of a synthetic GC, dexamethasone (100 nM, 10 min), which possesses no mineralocorticoid activity. The GC-elicited reversible intensification of synaptic transmission in the CA1 region was prevented by polymixin B (50 μM). Short-term influence of GC did not prevent the development of LTP. Prednisolone-induced changes in synaptic plasticity phenomena occurring in the CA1 region were prevented by a blocker of NMDA receptors, D-2-amino-5-phosphonovaleric acid (50 μM), but not by a blocker of AMPA receptors, 6,7-dinitroquinoxaline-2,3-dione (10 μM). Such modifications were moderated by inhibitors of calmodulin (trifluoperazine, 5 μM) and protein kinase C (polymixin B, 50 μM), but did not change under the influence of an inhibitor of calcineurin (cyclosporin A, 50 μM). It is supposed that an in vivo stress-induced rise in the GC level and an in vitro application of GC primarily intensify presynaptic release of glutamate, which activate postsynaptic high-affinity NMDA receptors. Activation of NMDA receptors facilitates both binding of type-II GC receptors in the cytoplasm of pyramidal neurons with the hormone and translocation of these receptors into the nucleus of these cells with subsequent suppression of transcription of neurotrophins. Inhibition of release of the latter underlies the GC-induced suppression of LTP and, at the same time, intensifies LTD and depotentiation of synaptic transmission in the CA1 region.

Functional Dynamics of the Central System of Regulation of Na + /Osmotic Homeostasis

In this paper, we analyze the phenomenon of functional dynamics (FD), i.e., modifications developing in neuronal networks of adult animals and resulting from the influence of long-lasting functional loadings on the systems, which are controlled with the involvement of these networks. Special attention is paid to the FD of the hypothalamic structures involved in the regulation of Na+/osmotic homeostasis. The paper is a “hybrid” of a review of existing data on the state of the problem and a brief description of the results obtained by the authors. Data on the structural manifestations of the FD (first of all, on changes in the glia–neuron relations) observed in the hypothalamic nuclei and structures connected with the hypothalamus after water-salt loadings, lactation, etc. are presented. The respective similar, in general, modifications related to changes in the physiological conditions that develop in the hippocampus and neocortex are also described. The relation of the structures of the preoptic/anterior hypothalamus (PO/AHTh) to the system of central control of osmotic homeostasis is discussed. A pharmacological experimental model providing creation of long-lasting shifts in the water/electrolyte balance, which was proposed by the authors, is described, and limits of its adequacy are discussed. The pattern of responses of the neurons, which form a neuronal network of the PO/AHTh, to hypo- and hyperosmotic discrete stimulations and modifications of these responses against the background of experimental hypo- or hypernatremia are analyzed. The authors propose an original scheme of a minimum mesh of the neuronal network under study allowed them to interpret the observed phenomena. Possible mechanisms of induction of the FD of the analyzed system considering the known mechanisms of modification of the efficiency of synaptic transmission are discussed.

Inhibition of nitric oxide synthesis and gene knockout of neuronal nitric oxide synthase impaired adaptation of mouse optokinetic response eye movements.

Nitric oxide (NO) plays a key role in synaptic transmission efficiency in the central nervous system. To gain an insight on the role of NO in cerebellar functions, we, here, measured the dynamics of the horizontal optokinetic response (HOKR) and vestibulo-ocular reflex (HVOR), and the adaptation of HOKR in mice locally injected with N(G)-monomethyl-L-arginine (L-NMMA) that inhibits NO synthesis and in mice devoid of neuronal nitric oxide synthase (nNOS). Local application of L-NMMA into the cerebellar flocculi induced no change in the dynamics of the HOKR but markedly depressed the adaptation of the HOKR induced by 1 hr of sustained screen oscillation. A slight difference was seen in the HOKR but not in the HVOR dynamics between nNOS(-/-) mutant and wild-type mice. One hour of sustained screen oscillation induced adaptation of the HOKR gains in wild-type mice but not in mutants. These observations suggest that NO is essential for the adaptation of the HOKR and that nNOS is the major enzyme for NO synthesis in the process.

GRASP-1: a neuronal RasGEF associated with the AMPA receptor/GRIP complex.

The PDZ domain-containing proteins, such as PSD-95 and GRIP, have been suggested to be involved in the targeting of glutamate receptors, a process that plays a critical role in the efficiency of synaptic transmission and plasticity. To address the molecular mechanisms underlying AMPA receptor synaptic localization, we have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. Overexpression of GRASP-1 in cultured neurons specifically reduced the synaptic targeting of AMPA receptors. In addition, the subcellular distribution of both AMPA receptors and GRASP-1 was rapidly regulated by the activation of NMDA receptors. These results suggest that GRASP-1 may regulate neuronal ras signaling and contribute to the regulation of AMPA receptor distribution by NMDA receptor activity.

Effects of chronic prenatal ethanol exposure on hippocampal glutamate release in the postnatal guinea pig

This study was designed to test the hypothesis that chronic prenatal ethanol exposure decreases basal and stimulated l-glutamate release in the hippocampus of young, postnatal guinea pigs. Timed, pregnant guinea pigs were randomly assigned to one of the following three chronic treatment groups: 4 g ethanol/kg maternal body weight/day, isocaloric-sucrose and pair-feeding to the ethanol group, and water. Each oral treatment was given daily throughout gestation. Spontaneous locomotor activity was increased on postnatal day (PD) 10, and brain and hippocampal weights were decreased on PD 12 in the offspring of the ethanol group compared with the isocaloric-sucrose/pair-fed and water groups. On PD 12, the 45 mM K +- and 10 μM veratridine-stimulated release of glutamate in transverse hippocampal slices was decreased in the ethanol group compared with the two control groups. This alteration in glutamate release produced by chronic prenatal ethanol exposure may decrease the efficiency of excitatory synaptic transmission in the hippocampus during postnatal life.

Spatial organization of quantum transmitter release and the role of cytoskeleton

Nowadays, basic features of the processes of chemical excitatory transmission between the neurons are well described by the quantum transmitter release theory. One of the fundamental statements of this theory is the following: the processes of transmitter release in central and peripheral neurons are spatially limited and occur in specialized presynaptic formations, active zones (AZ), where the contents of synaptic vesicles are released by exocytosis [1-4]. Such spatial limitation of the neurotransmitter secretion processes by the borders of AZ is related to the need to ensure a maximum efficiency of synaptic transmission. The aim of our research was to identify possible factors and presynaptic mechanisms responsible for such specialized spatial organization of the exocytotic processes within single AZ by using an electrophysiological technique, which allowed us to describe the topography of quantum secretion from motor nerve endings (NE). electrodes with smelted tips (diameter, 0.5-1.0 ~tm; resistance, 0.5-2.0 M~). Microelectrode tips were positioned on the NE in a triangular manner so that the distance between them was about 3-8 ~tm (Fig. 1A). Mutual disposition of the nerve terminal and microelectrodes was sketched. MEPC were recorded in the norm and alter colchicine applications (5 9 10 -3 mM). Signals recorded by each of the microelectrodes were amplified and measured using a computer-aided system. Then, the coordinates of quantum transmission release plots were determined based on correlation of the signal amplitudes recorded by each electrode and calculated with the use of a special program. It was suggested that the locus of signal generation on the postsynaptic membrane and the locus of transmitter release responsible for MEPC production spatially coincide [5]. The graphs, which reflect the disposition of quantum release in the NE, were plotted after processing of 200-5,500 MEPC signals. Statistical data processing was performed with the use of Origin 5.0 and Excel-2000,

Involvement of Different Types of Ca2+ Currents in the Control of the Efficiency of Inhibitory Synaptic Transmission between Cultured Hippocampal Neurons

We recorded evoked inhibitory post-synaptic currents (eIPSC) from a post-synaptic unit in a pair of synaptically connected cultured hippocampal neurons using a voltage-clamp technique in the whole-cell configuration and extracellular electrical stimulation of the pre-synaptic axon. Thirty-six neuronal pairs were examined. Dissimilar pharmacological sensitivities of eIPSC to a number of inorganic and organic blockers made it possible to estimate the involvement of different types of Ca2+ currents in Ca2+ entry into the presynaptic terminal and initiation of neurotransmitter release. Application of specific blockers of high-threshold Ca2+ channels allowed us to demonstrate that Ca2+ entry into presynaptic terminals of cultured hippocampal neurons is provided mostly by the system of high-threshold Ca2+ channels of the N- and P/Q-subtypes. The involvement of the L-subtype Ca2+ channels in the control of inhibitory transmission under study is insignificant.