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PubMed2006

Vesicular release of ATP at central synapses.

Adenosine triphosphate (ATP) acts as a fast excitatory transmitter in several regions of the central nervous system (CNS) including the medial habenula, dorsal horn, locus coeruleus, hippocampus, and somatosensory cortex. Postsynaptic actions of ATP are mediated through an extended family of P2X receptors, widely expressed throughout the CNS. ATP is released via several pathways, including exocytosis from presynaptic terminals and diffusion through large transmembrane pores (e.g., hemichannels, P2X(7) receptors, or volume-sensitive chloride channels) expressed in astroglial membranes. In presynaptic terminals, ATP is accumulated and stored in the synaptic vesicles. In different presynaptic terminals, these vesicles may contain ATP only or ATP and another neurotransmitter [e.g., gamma-amino-butyric acid (GABA) or glutamate]; in the latter case, two transmitters can be coreleased. Here, we discuss the mechanisms of vesicular release of ATP in the CNS and present our own data, which indicate that in central neuronal terminals, ATP is primarily stored and released from distinct pool of vesicles; the release of ATP is not synchronized either with GABA or with glutamate.

Adenosine Triphosphate↗
PubMed1995

Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels.

A site-directed anti-peptide antibody (anti-CNA1) directed against the alpha 1 subunit of class A calcium channels (alpha 1A) recognized a protein of approximately 190-200 kDa in immunoblot and immunoprecipitation analyses of rat brain glycoproteins. Calcium channels recognized by anti-CNA1 were distributed throughout the brain with a high concentration in the cerebellum. Calcium channels having alpha 1A subunits were concentrated in presynaptic terminals making synapses on cell bodies and on dendritic shafts and spines of many classes of neurons and were especially prominent in the synapses of the parallel fibers of cerebellar granule cells on Purkinje neurons where their localization in presynaptic terminals was confirmed by double labeling with the synaptic membrane protein syntaxin or the microinjected postsynaptic marker Neurobiotin. They were present in lower density in the surface membrane of dendrites of most major classes of neurons. There was substantial labeling of Purkinje cell bodies, but less intense staining of the cell bodies of hippocampal pyramidal neurons, layer V pyramidal neurons in the dorsal cortex, and most other classes of neurons in the forebrain and cerebellum. Scattered cell bodies elsewhere in the brain were labeled at low levels. These results define a unique pattern of localization of class A calcium channels in the cell bodies, dendrites, and presynaptic terminals of most central neurons. Compared to class B N-type calcium channels, class A calcium channels are concentrated in a larger number of presynaptic nerve terminals implying a more prominent role in neurotransmitter release at many central synapses.

Animals↗
PubMed1978

Calcium buffering in presynaptic nerve terminals. I. Evidence for involvement of a nonmitochondrial ATP-dependent sequestration mechanism.

A latent ATP-dependent Ca storage system is enriched in preparations of pinched-off presynaptic nerve terminals (synaptosomes), and is exposed when the terminals are disrupted by osmotic shock or saponin treatment. The data indicate that a fraction of the Ca uptake (measured with 45Ca) is associated with the intraterminal mitochondria; it is blocked by ruthenium red, by FCCP, and by azide + dinitrophenol + oligomycin. There is, however, a residual ATP-dependent Ca uptake that is insensitive to the aforementioned poisons; this (nonmitochondrial) Ca uptake is blocked by tetracaine, mersalyl and A-23187. Moreover, A-23187 rapidly releases previously accumulated Ca from these (nonmitochondrial) storage sites, whereas the Ca chelator, EGTA, does not. The proteolytic enzyme, trypsin, spares the mitochondria but inactivates the nonmitochondrial Ca uptake mechanism. Chemical measurements of total Ca indicate that the ATP-dependent Ca uptake at the nonmitochondrial sites involves the net transfer of Ca from medium to tissue fragments. This system can sequester Ca when the ambient-ionized Ca2+ concentration (buffered with EGTA) is less than 0.3 micrometer; brain mitochondria take up little Ca when the ionized Ca2+ level is this low. Preliminary subfractionation studies indicate that the nonmitochondrial Ca storage system does not sediment with synaptic vesicles. We propose that this Ca storage system, which has many properties comparable to those of skeletal muscle sarcoplasmic reticulum, may be associated with intraterminal smooth endoplasmic reticulum. This Ca-sequestering organelle may help to buffer intracellular Ca.

Adenosine Triphosphate↗
PubMed2001

Regulation of dendritic spine motility in cultured hippocampal neurons.

Regulation of dendritic spine motility was studied in dissociated cultures of the rat and mouse hippocampus, using green fluorescent protein-labeled neurons or neurons loaded with the calcium-sensitive dye Oregon Green-1. Cells were time-lapse-photographed on a confocal laser-scanning microscope at high resolution to detect movements as well as spontaneous fluctuations of intracellular calcium concentrations in their dendritic spines. Active presynaptic terminals attached to the spines were labeled with FM4-64, which marks a subset of synaptophysin-labeled terminals. Dendritic spines were highly motile in young, 4- to 7-d-old cells. At this age, neurons had little spontaneous calcium fluctuation or FM4-64 labeling. Within 2-3 weeks in culture, dendritic spines were much less motile, they were associated with active presynaptic terminals, and they expressed high rates of spontaneous calcium fluctuations. Irrespective of age, and even on the same dendrite, there was an inverse relationship between spine motility and presence of FM4-64-labeled terminals in contact with the imaged spines. Spine motility was blocked by latrunculin, which prevents actin polymerization, and was disinhibited by blockade of action potential discharges with tetrodotoxin. It is proposed that an active presynaptic terminal restricts motility of dendritic spines.

Action Potentials↗
PubMed1995

Pharmacological characterization of presynaptic calcium currents underlying glutamatergic transmission in the avian auditory brainstem.

We used whole-cell patch-clamp techniques on presynaptic terminals and postsynaptic neurons of the glutamatergic magnocellularis synapse in the chick auditory brainstem to study the effects of N, P, and L-type calcium channel blockers directly on presynaptic calcium currents and transmitter release. Presynaptic calcium currents and transmitter release were unaffected by nifedipine, blocked partially by omega-agatoxin IVA and completely by omega-conotoxin GVIA. The presynaptic calcium current is a low voltage-activated, noninactivating current and its block by omega-agatoxin IVA was not reversed by repeated depolarization of the presynaptic terminal. Thus, the presynaptic calcium current that underlies transmitter release at the chick magnocellularis synapse differs in some respects from N and P-type calcium currents described in vertebrate neuronal cell bodies.

Action Potentials↗
PubMed1992

The acoustic cortex in Alzheimer's disease.

The morphology of the acoustic cortex was studied in light and electron microscopy, in 6 post mortem cases of Alzheimer's disease. Silver impregnation techniques and routine stainings were applied for the study of the cytoarchitecture and the cellular morphology of the acoustic cortex. Samples from every part of the acoustic cortex were processed for electron microscopy. The morphological findings were correlated with those of normal controls of relevant age, as well as with the temporal isocortex of the anterior part of the superior temporal gyrus. Silver impregnation techniques revealed a marked loss of dendritic spines in the second, third and fourth cortical layers. An obvious decrease of the axonic collaterals of the large triangular and round neurons was also seen. Neurofibrillary tangles were found in the soma and the initial part of the axon in a large number of neurons, being more prominent in the neurons of the second and third cortical layers. Senile plaques were dispersed all over the acoustic cortex. Electron microscopy revealed numerous paired helical filaments (PHF) located mostly in the soma and the axons of the large neurons as well as numerous Hirano bodies. Synaptic alterations, such as polymorphism of the synaptic vesicles in the presynaptic terminals, dilatation of the synaptic cleft and accumulation of osmiophilic material in the postsynaptic terminals were seen in numerous synaptic profiles in the acoustic cortex. The rare dendritic spines developed synaptic contact practically only with one presynaptic terminal, in contrast to the normal controls which demonstrated numerous dendritic spines developing synapses with more than one presynaptic terminal. The morphological alterations in the acoustic cortex might explain the profound deficit in verbal memory and the language disturbances that are hallmarks in early cases of Alzheimer's disease.

Alzheimer Disease↗
PubMed2003

Modulation of synaptic transmission by the BCL-2 family protein BCL-xL.

BCL-2 family proteins are known to regulate cell death during development by influencing the permeability of mitochondrial membranes. The anti-apoptotic BCL-2 family protein BCL-xL is highly expressed in the adult brain and localizes to mitochondria in the presynaptic terminal of the adult squid stellate ganglion. Application of recombinant BCL-xL through a patch pipette to mitochondria inside the giant presynaptic terminal triggered multiconductance channel activity in mitochondrial membranes. Furthermore, injection of full-length BCL-xL protein into the presynaptic terminal enhanced postsynaptic responses and enhanced the rate of recovery from synaptic depression, whereas a recombinant pro-apoptotic cleavage product of BCL-xL attenuated postsynaptic responses. The effect of BCL-xL on synaptic responses persisted in the presence of a blocker of mitochondrial calcium uptake and was mimicked by injection of ATP into the terminal. These studies indicate that the permeability of outer mitochondrial membranes influences synaptic transmission, and they raise the possibility that modulation of mitochondrial conductance by BCL-2 family proteins affects synaptic stability.

Adenosine Triphosphate↗
PubMed2006

Constitutive sharing of recycling synaptic vesicles between presynaptic boutons.

The synaptic vesicle cycle is vital for sustained neurotransmitter release. It has been assumed that functional synaptic vesicles are replenished autonomously at individual presynaptic terminals. Here we tested this assumption by using FM dyes in combination with fluorescence recovery after photobleaching and correlative light and electron microscopy in cultured rat hippocampal neurons. After photobleaching, synapses acquired recently recycled FM dye-labeled vesicles originating from nonphotobleached synapses by a process requiring dynamic actin turnover. The imported vesicles entered the functional pool at their host synapses, as revealed by the exocytic release of the dye upon stimulation. FM1-43 photoconversion and ultrastructural analysis confirmed the incorporation of imported vesicles into the presynaptic terminal, where they mixed with the native vesicle pools. Our results demonstrate that synaptic vesicle recycling is not confined to individual presynaptic terminals as is widely believed; rather, a substantial proportion of recycling vesicles are shared constitutively between boutons.

Animals↗
PubMed1993

Axon hillocks and initial segments in spinal trigeminal nucleus with emphasis on synapses including axo-axo-axonic contacts.

As a part of a continuing study of the feline spinal trigeminal nucleus, the fine structure and synaptic arrangements on the axon hillock and axon initial segment of neurons in this region are described here. Transmission electron microscopy has been used to characterize qualitatively the axon hillock and initial segment and associated synapses in pars interpolaris. Axon hillocks and initial segments are easily identified in continuity with somata or as isolated profiles in the neuropil, and they receive synaptic contacts: these we regard as axo-axonic. The presynaptic terminals contain either mainly round or mainly flattened synaptic vesicles and have Type I (asymmetric) or Type II (symmetric) thickenings respectively at their contacts with the axon hillock or initial segment. I report here also the unusual arrangement of three separate axons in a serial synaptic complex. Some of the round vesicle Type I contacts onto the axon hillock-initial segment region also receive Type II contacts from one or more flattened vesicle terminals, thus forming an axo-axo-axonic complex. These flattened vesicle terminals lack the usual features of a presynaptic dendrite. It has been shown that in this nucleus some round vesicle terminals, especially those postsynaptic to flattened vesicle terminals, are primary afferents from the periphery. Therefore the round vesicle terminal presynaptic to the axon hillock-initial segment region, some of which are included in the axo-axo-axonic complex may also be a primary afferent directly contacting the spike generator area of the relay neuron and under presynaptic control of a flattened vesicle synapse. The latter may possibly be an intrinsic contact. This strategic situation of round vesicle terminals and the axo-axo-axonic complex at the axon hillock or initial segment has major implications relevant to the overall output of these neurons.

Animals↗
PubMed2005

Astrocytes regulate inhibitory synapse formation via Trk-mediated modulation of postsynaptic GABAA receptors.

Astrocytes promote the formation and function of excitatory synapses in the CNS. However, whether and how astrocytes modulate inhibitory synaptogenesis are essentially unknown. We asked whether astrocytes regulate the formation of inhibitory synapses between hippocampal neurons during maturation in vitro. Neuronal coculture with astrocytes or treatment with astrocyte-conditioned medium (ACM) increased the number of inhibitory presynaptic terminals, the frequency of miniature IPSCs, and the number and synaptic localization of GABA(A) receptor (GABA(A)R) clusters during the first 10 d in vitro. We asked whether neurotrophins, which are potent modulators of inhibitory synaptic structure and function, mediate the effects of astrocytes on inhibitory synapses. ACM from BDNF- or tyrosine receptor kinase B (TrkB)-deficient astrocytes increased inhibitory presynaptic terminals and postsynaptic GABA(A)R clusters in wild-type neurons, suggesting that BDNF and TrkB expression in astrocytes is not required for these effects. In contrast, although the increase in the number of inhibitory presynaptic terminals persisted, no increase was observed in postsynaptic GABA(A)R clusters after ACM treatment of hippocampal neurons lacking BDNF or TrkB. These results suggest that neurons, not astrocytes, are the relevant source of BDNF and are the site of TrkB activation required for postsynaptic GABA(A)R modulation. These data also suggest that astrocytes may modulate postsynaptic development indirectly by stimulating Trk signaling between neurons. Together, these data show that astrocytes modulate inhibitory synapse formation via distinct presynaptic and postsynaptic mechanisms.

Analysis of Variance↗
PubMed1997

Two components of transmitter release in retinal bipolar cells: exocytosis and mobilization of synaptic vesicles.

Ca2+-transmitter release coupling was examined using bipolar cells with large presynaptic terminals dissociated from the goldfish retina. Presynaptic Ca2+ current (I(Ca)) was recorded under the whole-cell voltage clamp. Release of excitatory amino acid transmitter was simultaneously monitored as the current through N-methyl-D-asperate (NMDA) receptors of reporter cells or as the membrane capacitance (C(m)) change associated with exocytosis. When I(Ca) was activated by a long depolarizing pulse, a double-peaked transmitter-induced current (I(tr)) was elicited in reporter cells. The rapid component of I(tr) was evoked immediately after the onset of depolarization, and was affected only slightly by intracellularly applied Ca2+ chelators. The delayed slow component of I(tr) was elicited during depolarization once a fixed amount of Ca2+ was accumulated in presynaptic terminals, and its appearance was suppressed or retarded by Ca2+ chelators. Two components of transmitter release were also recognized by monitoring C(m) changes elicited by the activation of I(Ca). These results suggest that bipolar cells have at least two pools of synaptic vesicles; a small, immediately releasable pool and a large releasable pool. The rapid and the delayed slow components of transmitter release may reflect exocytosis and mobilization of synaptic vesicles, respectively.

Animals↗
PubMed2004

Regulation of GABA release by depolarisation-evoked Ca2+ transients at a single hippocampal terminal.

We correlated dynamic changes in free cytosolic [Ca2+] ([Ca2+]i) within single presynaptic terminals of cultured hippocampal neurones with the postsynaptic GABA-mediated currents. The local changes in [Ca2+]i and evoked inhibitory postsynaptic currents (eIPSCs) were recorded simultaneously using Fura-2 fluorescence and whole-cell patch-clamp respectively. The Ca2+ signals and eIPSCs were evoked by direct extracellular electrical stimulation of a single presynaptic terminal by short depolarising pulses. The presynaptic Ca2+ transient was graded by varying the amplitude of extracellular stimulating pulses. The probability of the release event, P, estimated for each stimulation strength, reached a maximum (P=1) when the Ca2+ signal became maximal and remained at this level at higher stimulation strength, despite the subsequent decrease in the amplitude of the Ca2+ transient. A gradual, linear increase in stimulation amplitude (Vstim) resulted in a bell-shaped dependence of the averaged amplitudes of Ca2+ signals and corresponding averaged amplitudes of eIPSCs. Analysis of the eIPSC demonstrated that the decrease in both the mean eIPSC amplitude and the mean quantal content of release resulted from a reduction in the probability of multivesicular release, i.e. in the disappearance of failures and in the decrease of individual eIPSC amplitude. The Ca2+ signals of similar amplitude resulted in both random and determinate (non-random) neurotransmitter release. We conclude that depolarisation-induced elevation of [Ca2+]i within the terminal is necessary but not sufficient for activation of vesicular release of neurotransmitter.

Animals↗
PubMed1998

Calcium currents and calcium signaling in rod bipolar cells of rat retinal slices.

Combined electrophysiological and imaging techniques were used to study calcium currents (ICa) and their sites of origin at rod bipolar cells in rat retinal slices. We report here for the first time the successful whole-cell patch-clamp recording from presynaptic boutons that were compared with somatic recordings. TTX-resistant inward currents were elicited in response to depolarization. The kinetic and pharmacological properties of ICa were very similar for recordings obtained from the soma and the presynaptic terminals. ICa activated maximally between -30 and -20 mV was enhanced by Bay K 8644 and was blocked by isradipine and nifedipine. Peak amplitude and time to peak were -31.3 +/- 1.2 pA and 3.2 +/- 0.2 msec with somatic recordings (n = 54), whereas the corresponding values were -31.6 +/- 6.1 pA and 3.2 +/- 0.7 msec in recordings obtained directly from terminals (n = 6). ICa showed little inactivation during sustained depolarizations. No T-type ICa was observed with depolarizations from -90 mV. Concomitant with Ca2+ entry, depolarization induced the appearance of transient outward currents that resembled IPSCs and were blocked by GABA and glycine receptor antagonists, suggesting that they arise from activation of amacrine feedback synapses. Upon depolarization, intracellular Ca2+ ([Ca2+]i) rises were restricted to the presynaptic terminals with no somatic or axonal changes and were linearly dependent on pulse duration when using a low-affinity Ca2+ indicator. In cone bipolar cells, ICa inactivated markedly, and [Ca2+]i rises occurred in the axon, as well as in the presynaptic terminals.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Comparative immunohistochemical study on synaptophysin expression in the anterior horn of post-poliomyelitis and sporadic amyotrophic lateral sclerosis.

This report concerns a comparative study of alterations of anterior horn presynaptic terminals in post-poliomyelitis and sporadic amyotrophic lateral sclerosis (S-ALS). Synaptophysin (SP) served as a marker for presynaptic terminals; immunohistochemical techniques were used throughout. Spinal cords from six individuals without neurological disease served as controls. Localized and well-delineated anterior horn neuropil areas with decreased SP immunoreactivity were observed in the five cases of post-poliomyelitis studied. These areas had few remaining neurons but had pronounced reactive gliosis which corresponded to those areas in which typical poliomyelitis lesions were present. Normal neuronal SP expression was preserved in the adjacent, non-affected areas. However, a small region with increased SP levels was observed in one case. By comparison, the decrease in anterior horn SP immunoreactivity was diffuse in the four S-ALS patients studied. The present data suggest that presynaptic terminals ending at the somata and processes of affected anterior horn neurons located in the area of the acute infection are degenerate in post-poliomyelitis. By contrast, in S-ALS the terminals ending at distal dendrite portions tend to be severely degenerate, while those terminating at the proximal portions of the neuron are relatively well preserved. Our results thus provide additional evidence that the pathogenesis of the post-poliomyelitis state differs from that of ALS.

Aged↗
PubMed1984

Divalent cations differentially support transmitter release at the squid giant synapse.

The ability of Ca, Sr and Ba ions to support transmitter release was studied at the squid giant synapse by examining their respective actions on presynaptic current and post-synaptic responses. Transmitter-induced post-synaptic currents were smaller in Sr- than in Ca- containing solutions, and much smaller in Ba-containing solutions. The time course and amplitude of spontaneous miniature post-synaptic potentials were similar in the presence of all three divalent ions. Sr or Ba substitution has little effect on the resting potential of presynaptic terminals. In Sr-containing solutions, action potentials were similar in amplitude and time course to those recorded in Ca. Ba slightly prolonged action potential duration but had no effect on amplitude. Voltage-clamped presynaptic terminals exhibited inward Ca, Sr or Ba currents which were apparently carried through Ca channels. These currents were similar in amplitude and time course in all three ions, being somewhat larger in Ba. Although presynaptic currents were similar in these ions, transmitter release induced by these currents depended upon the divalent species entering the presynaptic terminal. Release was greatest in response to presynaptic current carried by Ca and smallest in response to current carried by Ba. Transfer curves relating presynaptic current to post-synaptic potential were sigmoidal in all three ions, and exhibited limiting slopes of approximately 2. Divalent cations differentially support transmitter release at the squid giant synapse in the sequence Ca greater than Sr much greater than Ba. The differential efficacy of the divalent cations is not due to post-synaptic alterations, presynaptic potential changes or differences in presynaptic divalent cation conductances. This sequence may reflect the cation selectivity of the exocytotic process responsible for transmitter release.

Action Potentials↗
PubMed1983

Electronmicroscopic study of somatostatin-containing neurons in rat arcuate nucleus with special reference to neuronal regulation.

After an intraventricular administration of colchicine, the arcuate nucleus of rat hypothalamus was examined light and electron microscopically by pre-embedding immunohistochemistry for somatostatin. The arcuate nucleus exhibited numerous immunoreactive cell bodies and dense networks of immunoreactive fibers. The fibers appeared to surround immunonegative cell bodies. The immunoreactive cell bodies were multipolar in shape and projected immunoreactive processes to some extent. The immunoreactive cell bodies and fibers received synaptic contacts by immunonegative fiber terminals containing a large number of synaptic clear vesicles. Similarly, immunoreactive somatostatin fibers appeared to terminate upon other immunonegative cell bodies and fibers. The immunoreactive presynaptic terminals contain several labeled granules and numerous synaptic vesicles. In close proximity to these immunolabeled terminals, non-labeled presynaptic terminals were also observed upon the immunonegative cell bodies and fibers. This suggests that in the arcuate nucleus neurons regulated by somatostatin neurons are also under the control of other types of neurons.

Animals↗
PubMed1986

Posthatching development of synapses in the neuropil of nucleus rotundus of the zebra finch: a quantitative electron microscopic study.

The development and maturation of synapses in the nucleus rotundus of the zebra finch were examined at 1, 5, 10, 20, and 100 days posthatching. Quantitative ultrastructural techniques were applied to investigate synaptic density, size of presynaptic terminals, and length of postsynaptic thickenings. During development there is a steady increases in the number of synapses and an enlargement of the presynaptic terminals. The length of the postsynaptic thickenings, however, decreases significantly during posthatching development. All three parameters reach adult values within 20 days of age. A close relationship was found between the enlargement of the presynaptic terminals and the increase in the number of contact zones up to the 20th day. The general feature of this developmental progress is in good agreement with biochemical and, to a certain extent, behavioral studies.

Animals↗
PubMed1989

Three potassium currents in mouse motor nerve terminals.

A study of the K conductance of the presynaptic membrane has been performed in the triangularis sterni muscle of the mouse. External currents generated in the presynaptic terminals upon invasion by action potentials have been recorded using microelectrodes inserted into the perineurium of preterminal nerve bundles. The voltage-dependent K current could be pharmacologically dissected into fast (IKf) and slow (IKs) components. While both are sensitive to 3,4-diaminopyridine (3,4-DAP), only IKf is sensitive to tetraethylammonium (TEA). Uranyl (100-200 microM) and guanidine (5-10 mM) produced a near complete block of IKf and IKs, which can explain their facilitatory effect upon transmitter release. The third K current of presynaptic terminals is Ca2+-dependent, but was activated also by Sr2+. This current could be suppressed by nanomolar doses of charybdotoxin; it is also sensitive to TEA but not to 3,4-DAP, uranyl or guanidine.

4-Aminopyridine↗