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PubMed2006

Induction of neocortical long-term depression results in smaller movement representations, fewer excitatory perforated synapses, and more inhibitory synapses.

Long-term depression (LTD) is one of the most widely investigated models of the synaptic mechanisms underlying learning and memory. Previous research has shown that induction of LTD in the neocortex decreases measures of pyramidal cell dendritic morphology in both layers III and V. Here, we investigated the effects of LTD induction on 1) the time course of recovery of synaptic efficacy, 2) movement representations, 3) cortical thickness and layer V neuron density, and 4) the density of excitatory and inhibitory synapses in layer V of sensorimotor neocortex. Rats carried a stimulating electrode in the midline corpus callosum and a recording electrode in the right sensorimotor neocortex. Each rat received either low-frequency stimulation composed of 900 pulses at 1 Hz or handling daily for a total of 20-25 days. Callosal-neocortical evoked potentials were recorded in the right hemisphere before and after stimulation or handling. Our results show that LTD induction lasts for 3 weeks and results in smaller motor maps of the caudal forelimb area. We did not observe any reduction in neocortical thickness or neuron density. There was a reduction in the density of excitatory perforated synapses and an increase in the density of inhibitory synapses in layer V of the sensorimotor neocortex, thereby providing a general mechanism for the reduction in motor map size. This study sheds light on the interaction between an artificial model of learning, receptive field characteristics, and synaptic number in the sensorimotor cortex.

Animals↗
PubMed2004

Transiently higher release probability during critical period at thalamocortical synapses in the mouse barrel cortex: relevance to differential short-term plasticity of AMPA and NMDA EPSCs and possible involvement of silent synapses.

Thalamocortical connections undergo remarkable plasticity during the critical period and mounting evidence serves to demonstrate that the activation of silent synapses at postsynaptic sites is an important underlying mechanism in this process. However, relatively little is known about the nature of the presynaptic properties. In the present study, we examined the release probability (Pr) of thalamocortical synaptic terminals on a layer IV neuron in the developing mouse barrel cortex. Using the conventional paired-pulse ratio (PPR) method, both AMPA and NMDA receptor-mediated PPR were observed during development. We found that the NMDA PPR increased gradually (thus, a reduction in Pr) from postnatal day (P)4 to P22 but, unexpectedly, the AMPA PPR exhibited a simultaneous decrease. We then used an additional method for assessing release probability, the observation of a progressive block of NMDA receptor-mediated EPSCs using MK-801. With this method, we were able to identify two classes of terminals with high or low probabilities of release. Interestingly, the higher release showed a reduction in probability during the critical period, consistent with the NMDA PPR results. We confirmed that the discrepancy between the NMDA and the AMPA PPR results was due to the existence of silent, or NMDA-only, synapses, as suggested in previous literature. By analysing the correlation between the NMDA or AMPA PPR and the PPR discrepancy, we discuss the hypothesis that the terminals with transiently higher probability of release were found preferentially on silent synapses. Our results suggest that these presynaptic sites may also have an active role in plasticity by working concomitantly with postsynaptic sites during the critical period.

Age Factors↗
PubMed1995

Properties of transmission at a giant glutamatergic synapse in cerebellum: the mossy fiber-unipolar brush cell synapse.

1. The synaptic activation by mossy fibers (MFs) of unipolar brush cells (UBCs) in the vestibular cerebellum (nodulus and uvula) was examined using patch-clamp recording methods in thin, rat cerebellar slices with Lucifer yellow-filled pipettes for subsequent fluorescence microscopic verification of the cell morphology. 2. UBCs were distinguished from adjacent granule cells in thin cerebellar slices in the uvula and nodulus regions by their larger soma diameters and short dendritic brush, greater whole-cell capacitance, and a prolonged, biphasic excitatory postsynaptic current (EPSC) to stimulation of MFs. 3. Thin-section transmission electron micrographs of the MF-UBC synapse displayed an unusually extensive area of synaptic apposition estimated to measure 12-40 microns2. The majority of UBCs was innervated by a single MF. At high magnification, individual clusters of presynaptic vesicles could be discerned, separated by regions of presynaptic membrane lacking vesicles, but apposed to continuous regions of postsynaptic density. Thus, after release, transmitter diffusion from the synaptic cleft must traverse considerable stretches of postsynaptic membrane before escape into extracellular space. In contrast, MF-granule cell synapses in these cerebellar regions resembled glutamate synapses in other brain regions in that the total synaptic area measured < or = 4 microns2. These synaptic junctions were flanked by short stretches of unspecialized plasma membrane, providing a short (0.5 micron) diffusional path from the site of neurotransmitter release to a branch point of the extracellular space. 4. The MF-evoked EPSC in UBCs was composed of a fast (10-90% rise time: 0.70 ms) and slow (10-90% rise time: 395 ms; 10-90% decay time: 3.1 s) component. The fast component was blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/KA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and displayed linear current-voltage (I-V) relations in the presence or absence of external magnesium. 5. The slow EPSC was also mediated by glutamate receptors, but in most neurons both AMPA/KA and N-methyl-D-aspartate (NMDA) receptors contributed to the slow EPSC, with the contribution of NMDA receptors predominating in the majority of cells. Consequently, although all cells displayed linear I-V relations in Mg(2+)-free saline, cells in which the slow EPSC was predominently mediated by NMDA receptors exhibited voltage-dependent rectification in the presence of external Mg2+ (1 mM). 6. With increasing postnatal age (10-30 d), the contribution made to the slow EPSC by NMDA receptors declined, with a reciprocal increase in the contribution being made by AMPA/KA receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed2004

Regionally specific distribution of corticospinal synapses because of activity-dependent synapse elimination in vitro.

We have shown previously that the corticospinal tract (CST) with functional connections can be reconstructed in vitro in slice cocultures. Using that system, we stimulated the deep cortical layer and recorded field EPSPs (fEPSPs) along a 100 microm-interval lattice in the spinal gray matter. The specific, spatial synapse distribution on the dorsal side at 14 d in vitro (DIV) basically corresponded to the in vivo area in which CST axons terminate. Anterograde labeling of corticospinal axons with biocytin showed a similar terminal distribution on that side. In vitro development of synapse spatial distribution was investigated. fEPSPs were recorded all across the gray matter at 7 DIV, but amplitudes began to decrease on the ventral side at 9 DIV, dorsal-dominant distribution being nearly complete at 14 DIV. Anterograde labeling showed that the decrease in fEPSP amplitudes was associated with a decrease in the number of axon terminals on the ventral area. Decreases in the synaptic responses and terminals were blocked by applications of D-2-amino-5-phosphonovaleric acid and tetrodotoxin, whereas 6-cyano-7-nitroquinoxaline-2,3-dione had a partial effect. These findings suggest that this regressive event, which occurs during development, is activity and NMDA dependent. Retrograde labeling with two colors of beads and an electrophysiological study that investigated the axon reflex showed that at 7 DIV most corticospinal neurons project to both the ventral and dorsal spinal cord, indicating that synapse decrease on the ventral side is attributable primarily to axon branch elimination rather than to death of cortical cells that send axons solely to that side.

Animals↗
PubMed2003

Synapse density regulates independence at unitary inhibitory synapses.

Neurotransmitter transporters may promote synapse specificity by limiting spillover between release sites. At GABAergic synapses, transport block prolongs synaptic responses when many inputs are activated, yet it is unclear whether transporters alter signaling by single axons. We found that unitary IPSCs generated by paired recordings between hippocampal interneurons and granule cells could be either prolonged or totally unaffected by block of GABA transporters. This variability was explained by the density of active release sites rather than the number of active sites. Prolongation by transport block required release from multiple sites and was enhanced by repetitive activation. Furthermore, transport-sensitive unitary IPSCs were accelerated when the release probability was reduced, indicating that cross talk prolonged the time course of IPSCs even when transport was intact. Our results suggest that the release site density regulates the degree of cross talk as well as the contribution of transporters to GABA clearance. Thus, interplay between release site density and transporter action determines the independence of unitary inhibitory synapses.

Animals↗
PubMed1994

Proteolytic activity, synapse elimination, and the Hebb synapse.

The Hebb synapse has been postulated to serve as a mechanism subserving both regulation of synaptic strength in the adult nervous system (long-term potentiation and depression) and developmental activity-dependent plasticity. According to this model, pre- and postsynaptic temporal concordance of activity results in strengthening of connections, while discordant activity results in synapse weakening. Evidence is presented that proteases and protease inhibitors may be involved in modification of synaptic strength. This leads to a modification of the Hebb assumptions, namely that postsynaptic activity results in protease elaboration with a consequent general reduction of synaptic connections to the active postsynaptic element. Further, presynaptic activity, if strong enough, induces local release of a protease inhibitor, such as protease nexin I, which neutralizes proteolytic activity and produces a relative preservation of the active input. This formulation produces many of the effects of the classical Hebbian construction, but the protease/inhibitor model suggests additional specific mechanistic features for activity-dependent plasticity.

Amyloid beta-Protein Precursor↗
PubMed1992

Freeze-etched postsynaptic membranes in the visual cortex reveal different types of synapses including mixed synapses.

The intramembranous structure of the postsynaptic membranes in the rat visual cortex was examined. Simple, complex and mixed synapses were differentiated according to the shape of the postsynaptic particle aggregations. The present data support the existence of all intermediate stages schematically presented in the hypothesis describing a synapse division. The advantage of the freeze-etching technique for the study of the shape of the active zones is emphasized.

Animals↗
PubMed1994

Metabotropic glutamate receptor-induced disinhibition is mediated by reduced transmission at excitatory synapses onto interneurons and inhibitory synapses onto pyramidal cells.

Previous studies suggest that activation of metabotropic glutamate receptors (mGluRs) reduces GABA-mediated synaptic inhibition in area CA1 of the hippocampus. However, the mechanisms involved in this disinhibition are not known. We report that mGluR activation reduces both the GABAA and GABAB receptor-mediated components of evoked inhibitory postsynaptic potentials (IPSPs) by reducing transmission at excitatory synapses onto inhibitory interneurons and inhibitory synapses onto CA1 pyramidal cells.

Animals↗
PubMedDate not supplied

[Three-dimensional reconstruction of synapse and dendritic spines in the hippocampus of rats and ground squirrels: new paradigms of the structure and function of a synapse].

The article reviews the literature data and results obtained by the authors concerning synaptic plasticity and remodeling of synaptic organelles in the central nervous system. Modern techniques of laser scanning confocal microscopy and serial thin sectioning for in vivo and in vitro studies of dendritic spines including a correlation between morphological changes and synaptic transmission efficiency are discussed, particularly, in relation to long-term potentiation. Organization of different types of dendritic spines and involvement of filopodia in spine genesis are examined. Significance of serial ultrathin sections for unbiased quantitative stereological analysis and three-dimensional reconstructions is discussed. The contact of one dendritic spine with two presynaptic boutons (multiple synapses) on both CA1 mushroom dendritic spines is discussed. The analyzed findings suggest new ideas for organization and functioning of synapses.

Animals↗
PubMed1977

Monoaminergic synapses, including dendro-dendritic synapses in the rat substantia nigra.

Intraventricular administration of 1 or 2 mg of the osmiophilic "false transmitter" 5-hydroxydopamine (5-OHDA) was used to label monoamine storage and release sites in the rat substantia nigra. Vesicles containing unusually dense cores indicative of the presence of the marker were seen forming from the Golgi apparatus in the cell bodies of medium-sized neurons of the substantia nigra, pars compacta, and from smooth endoplasmic reticulum in the dendrites of those neurons and in small unmyelinated axons of unknown origin. In serial sections, both axons and dendrites containing synaptic vesicles marked with 5-OHDA were seen to form synapses "en passage" in pars compacta, and some presynaptic dendrites containing vesicles filled by the marker were also observed to form contacts with dendrites in pars reticulata. The only identified postsynaptic elements engaging in monoaminergic synapses in the substantia nigra were dendrites of medium-sized pars compacta neurons.

Animals↗
PubMed1989

Differential effects of phospholipase inhibitors in long-term potentiation in the rat hippocampal mossy fiber synapses and Schaffer/commissural synapses.

Bath application of the inhibitors of phospholipases, nordihydroguaiaretic acid (NDGA) and p-bromo-phenacyl bromide (BPB), to the rat hippocampal slices suppressed long-term potentiation (LTP) in Schaffer/commissural-CA1 pyramidal synapses. On the other hand, neither of the two inhibitors suppressed LTP in mossy fiber-CA3 pyramidal cell synapses. BPB did not suppress phosphatidylinositol-specific phospholipase C (PI-PLC) activity of the slices. These results suggested that the mechanisms of LTP were quite different in the CA1 and CA3 subfields of rat hippocampus: in CA1, the involvement of an arachidonate metabolism was strongly suggested, whereas in CA3, an arachidonic acid cascade may not be necessary for LTP.

Acetophenones↗
PubMed2001

Visualizing synapse formation and remodeling: recent advances in real-time imaging of CNS synapses.

The formation and maintenance of synaptic connections are critical in the development and plasticity of the central nervous system (CNS). Until recently, there have been few studies that followed the molecular sequences of the CNS synapse formation and maintenance. This situation changed dramatically after the introduction of green fluorescent protein (GFP)-based fluorescent probes and the development of lipophilic tracers of endocytotic membranes. These techniques enabled us to visualize presynaptic and postsynaptic structures in living neurons and illustrated active transport and remodeling of synaptic components. Furthermore, recent attempts to identify correlation between presynaptic and postsynaptic morphogenesis suggested very rapid time course of synapse formation at the individual axo-dendritic contact sites. These recent works clearly demonstrated the power of real-time imaging studies. Development of a wide variety of fluorescent probes and advances in the imaging techniques in future will further extend our knowledge on the molecular events that take place in the process of the development and maturation of synaptic junctions.

Animals↗
PubMed2006

Immunological synapse arrays: patterned protein surfaces that modulate immunological synapse structure formation in T cells.

T cells are activated by recognition of foreign peptides displayed on the surface of antigen presenting cells (APCs), an event that triggers assembly of a complex microscale structure at the T cell-APC interface known as the immunological synapse (IS). It remains unresolved whether the unique physical structure of the synapse itself impacts the functional response of T cells, independent of the quantity and quality of ligands encountered by the T cell. As a first step toward addressing this question, we created multicomponent protein surfaces presenting lithographically defined patterns of tethered T cell receptor (TCR) ligands (anti-CD3 "activation sites") surrounded by a field of tethered intercellular adhesion molecule-1 (ICAM-1), as a model substrate on which T cells could be seeded to mimic T cell-APC interactions. CD4(+) T cells seeded on these surfaces polarized and migrated; on contact with activation sites, T cells assembled an IS with a structure modulated by the physical pattern of ligand encountered. On surfaces patterned with focal spots of TCR ligand, T cells stably interacted with activation sites, proliferated, and secreted cytokines. In contrast, T cells interacting with activation sites patterned to preclude centralized clustering of TCR ligand failed to form stable contacts with activation sites, exhibited aberrant PKC- clustering in a fraction of cells, and had significantly reduced production of IFN-gamma. These results suggest that focal clustering of TCR ligand characteristic of the "mature" IS may be required under some conditions for full T cell activation.

Animals↗
PubMed1990

Anti-GABA antibodies label a subpopulation of chemical synapses which modulate an electrical synapse in crayfish.

Antibodies raised against gamma-aminobutyric acid (GABA) were used to stain sections from the crayfish abdominal nervous system, and the sections were examined under the electron microscope using a protein-A/gold conjugate secondary label. Sections were taken through the third ganglionic root, and through the interganglionic connective at the base of the third root posterior to the ganglia. The third root contains two very large motor axons, a non-GABAergic excitor (Motor Giant; MoG), and a GABAergic inhibitor (Flexor Inhibitor; FI). Only one of the two large axons stained positively for GABA, confirming that the antibody has high specificity for GABAergic neurones. The MoG is driven by powerful electrical synapses from the giant fibres, but also receives inhibitory chemical synaptic input which can gate the excitatory input. There is no physiological evidence for any other form of chemical input. However, at the ultrastructural level, the MoG is postsynaptic to three types of chemical profiles; SE-type containing round agranular vesicles, SI-type containing pleomorphic vesicles, and SM-type containing a mixture of round agranular and dense-cored vesicles. There is a highly differentiated staining pattern of these three synaptic types. Only the SI-type profiles stain positively with the GABA antibody, while the SE- and SM-type do not show significant staining. This suggests that the MoG can under some circumstances receive chemical input other than GABAergic inhibitory input. These other types of input have yet to be physiologically identified.

Animals↗
PubMed1987

Saphenous has weak ineffective synapses in sciatic territory of rat spinal cord: electrical stimulation of the saphenous or application of drugs reveal these somatotopically inappropriate synapses.

In a previous paper, we showed that chronic denervation of the sciatic nerve for more than 21 days in adult rats caused expansion of the saphenous nerve into sciatic territory in the spinal cord (medial L4, L5 and L6). To try to explain this expansion in the present paper, we tested the hypothesis that weak ineffective synapses of saphenous terminals are always present in sciatic territory. For this purpose the sciatic nerve was acutely denervated, the cord mapped with microelectrodes and responses evoked in single cells with natural (mechanical cutaneous) or electrical (pulses to saphenous nerve) stimulation. In the sciatic territory, no natural responses occurred but electrically evoked responses from the saphenous were everywhere. When drugs were applied to potentiate synaptic activity, many of the silent neurons in the sciatic territory in L4, L5 and L6 responded to natural inputs mediated by the saphenous. Picrotoxin was more effective than 4-aminopyridine which was more effective than strychnine in expressing these weak somatotopically inappropriate saphenous inputs. All together, these results support the hypothesis that weak ineffective saphenous inputs exist in sciatic territory of the spinal cord. They can be artificially expressed with electrical volleys or chemical potentiation and may be naturally expressed several weeks after chronic lesions of the sciatic nerve.

4-Aminopyridine↗
PubMed1997

Centenary of the synapse: from Sherrington to the molecular biology of the synapse and beyond.

Few concepts have meant more to neuroscience than the synapse, commonly understood to mean the junction between two excitable cells. The term was introduced by Charles Sherrington in 1897. The centenary of this event is an appropriate time to review the term's origins and utility. There are some surprises. The term didn't actually come from him. His concept was more functional than structural. The pioneering physiological and structural studies in the 1950s in fact did not lead to a rigorous definition. There is still confusion on how to define neurotransmitters. As molecular biological approaches are increasingly refining the concept of a fundamental synaptic unit, many types of neuronal interactions are appearing that do not fit with the synaptic concept. Are the neural circuits underlying behaviour strictly synaptic? In dealing with these questions, a longer perspective is useful for understanding how the term arose, how it has evolved to the present, and what kinds of challenges may be coming in the future.

Animals↗
PubMed2002

Synapse-independent and synapse-dependent apoptosis of cerebellar granule cells in postnatal rabbits occur at two subsequent but partly overlapping developmental stages.

It has long been known that cells in the external granular layer die during postnatal development of the cerebellum. More recent findings indicate that at certain developmental stages, cell death occurs upon activation of an apoptotic program. We show that cerebellar granule cells in rabbits undergo programmed cell death at two different stages of maturation. At postnatal day 5 (P5), granule cell precursors and pre-migratory granule cells in the external granular layer incorporate the S-phase markers 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine with a pattern that is dependent upon the interval between the administration of the two tracers. Within 12-24 h after proliferation a significant number of labeled cells show typical ultrastructural alterations of apoptosis. DNA electrophoresis and cleavage of poly-ADP-ribose polymerase confirm the activation of the apoptotic machinery. After Southern blotting and immunodetection, incorporated 5-bromo-2'-deoxyuridine is present at the level of low size DNA oligomers as soon as 12 h after cell division. Therefore, this apoptotic phase is intrinsic to external granular layer neurons and independent of synaptic interactions with targets.Apoptotic cells, although fewer in number, are detected also in the internal granular layer and tend to increase from P5 to P10. It seems unlikely that these cells undergo DNA fragmentation in the external granular layer and subsequently migrate to their final destination, considering the data on cell cycle kinetics and the rapid tissue clearance by the glia. Parallel fiber-Purkinje spine synapses are already present in the molecular layer at P5. Therefore, the post-migratory granule cells likely undergo apoptosis as a failure to make proper synaptic contacts in the forming molecular layer. We conclude that the massive apoptosis of pre-migratory cells likely has a role in regulating the size of this rapidly expanding population of pre-mitotic neurons. The less tumultuous cell death of post-mitotic granule cells in the internal granular layer appears to be linked to the formation of the mature synaptic circuitry of the developing cerebellar cortex.

Aging↗
PubMed2003

Presynaptic activation of silent synapses and growth of new synapses contribute to intermediate and long-term facilitation in Aplysia.

The time course and functional significance of the structural changes associated with long-term facilitation of Aplysia sensory to motor neuron synaptic connections in culture were examined by time-lapse confocal imaging of individual sensory neuron varicosities labeled with three different fluorescent markers: the whole-cell marker Alexa-594 and two presynaptic marker proteins-synaptophysin-eGFP to monitor changes in synaptic vesicle distribution and synapto-PHluorin to monitor active transmitter release sites. Repeated pulses of serotonin induce two temporally, morphologically, and molecularly distinct presynaptic changes: (1) a rapid activation of silent presynaptic terminals by filling of preexisting empty varicosities with synaptic vesicles, which parallels intermediate-term facilitation, is completed within 3-6 hr and requires translation but not transcription and (2) a slower generation of new functional varicosities which occurs between 12-18 hr and requires transcription and translation. Enrichment of empty varicosities with synaptophysin accounts for 32% of the newly activated synapses at 24 hr, whereas newly formed varicosities account for 68%.

Animals↗