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PubMed2004

In vivo trafficking and targeting of N-cadherin to nascent presynaptic terminals.

N-cadherin is a prominent component of developing and mature synapses, yet very little is known about its trafficking within neurons. To investigate N-cadherin dynamics in developing axons, we used in vivo two-photon time-lapse microscopy of N-cadherin--green fluorescent protein (Ncad-GFP), which was expressed in Rohon-Beard neurons of the embryonic zebrafish spinal cord. Ncad-GFP was present as either stable accumulations or highly mobile transport packets. The mobile transport packets were of two types: tubulovesicular structures that moved preferentially in the anterograde direction and discrete-punctate structures that exhibited bidirectional movement. Stable puncta of Ncad-GFP accumulated in the wake of the growth cone with a time course. Colocalization of Ncad-GFP puncta with synaptic markers suggests that N-cadherin is a very early component of nascent synapses. Expression of deletion mutants revealed a potential role of the extracellular domain in appropriate N-cadherin trafficking and targeting. These results are the first to characterize the trafficking of a synaptic cell-adhesion molecule in developing axons in vivo. In addition, we have begun to investigate the cell biology of N-cadherin trafficking and targeting in the context of an intact vertebrate embryo.

Animals↗
PubMed1995

Hyperosmotic activation of transmitter release from presynaptic terminals onto retinal ganglion cells.

A method for evoking neurotransmitter release without light stimulation has been developed and applied to a retinal slice preparation of the tiger salamander (Ambystoma Tigrum). This method utilizes a micropipette containing hyperosmotic levels of sucrose in Ringer, positioned within the inner plexiform layer (IPL) under visual control. Intermittent pressure (between 0.1 and 2 bars) applied to the pipette evoked release of neurotransmitters which were evaluated with whole-cell recording (WCR) technique applied to cells in the ganglion cell layer. Pharmacological studies were used to characterize the properties of the hyperosmotic sucrose-evoked response (HSER) and in some cases, we compared the HSER with synaptic currents evoked by light stimulation. The HSER typically consisted of both inhibitory and excitatory components with a reversal potential in between that for chloride (approximately -60 mV) and non-specific cation channels (approximately 0 mV). Relatively pure inhibition or excitation could be revealed through pharmacological techniques by blocking the inhibition with picrotoxin/strychnine or by blocking the glutamatergic neurotransmission with D-AP7 (D-2-amino-7-phosphonoheptanoate) and NBQX (2,3-dihydroxy-6-nitro-sulfamoyl -benzo (F) quinoxaline). A comparison of light-evoked responses (LER) and the HSER suggested that they activate the same pool of releasable neurotransmitter.

2-Amino-5-phosphonovalerate↗
PubMed2005

Kainate-induced zinc translocation from presynaptic terminals causes neuronal and astroglial cell death and mRNA loss of BDNF receptors in the hippocampal formation and amygdala.

To evaluate the potential role of endogenous zinc in the pathophysiology of epilepsy, we injected kainic acid into the medial septum, which evokes seizure activity and delayed hippocampal degeneration. Different approaches were used. In the hippocampus, we found a movement of zinc from the synaptic compartment to CA1 pyramidal neurons and astrocytes after kainate. The same was true in the amygdala. We found that in those areas showing intense zinc bleaching there was also a loss of reactive astrocytes, which supports the view that release of synaptic zinc induces astrocytic cell death. We have also tested whether the kainate-induced zinc movement from the synaptic compartment to neuronal or glial cells alters the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, trkB. There was a prominent loss of expression of trkB mRNA in areas that coincided precisely with those displaying astrocyte loss and zinc bleaching. In the amygdala, these events were accompanied by a high upregulation of BDNF mRNA. To demonstrate further a role of synaptic zinc in hippocampal pathology, we used two different approaches. We first injected different doses of zinc chloride in the CA1 area. At lower doses (0.1-10 nmol), zinc chloride selectively induced apoptosis in CA1 pyramidal neurons and dentate granular neurons. In a second approach, we found that hippocampal zinc chelation was effective in protecting CA1 pyramidal neurons against kainate-induced cell death.

Amygdala↗
PubMed2002

Calcium channel subtypes on single GABAergic presynaptic terminal projecting to rat hippocampal neurons.

High voltage-activated Ca(2+) channel subtypes triggering GABA release from nerve terminals (boutons) projecting to rat hippocampal CA1 pyramidal neurons were studied. Evoked GABAergic inhibitory postsynaptic currents (eIPSCs) were recorded in response to focal stimulation of single boutons in mechanically dissociated neurons and in response to stimulation of nerve bundle in slice preparations. Nilvadipine (3 micro M), an L-type Ca(2+) channel blocker, completely inhibited eIPSCs evoked by stimulation of single boutons, but had no effect on eIPSCs evoked by stimulation of nerve bundle at low frequencies. Nilvadipine (3 micro M) did, however, prevent the potentiation of eIPSC amplitude following high-frequency stimulation of nerve bundles in the slice preparation. omega-Conotoxin-GVIA (3 micro M), an N-type Ca(2+) channel blocker, and omega-agatoxin-IVA (0.3 micro M), a P/Q-type Ca(2+) channel blocker, completely inhibited single bouton evoked eIPSCs in 33.3 and 83.3% of recordings, respectively. In response to low-frequency nerve bundle stimulation in the slice preparation, omega-conotoxin-GVIA (3 micro M), omega-agatoxin-IVA (0.1 micro M) both partially reduced eIPSC amplitude, with the residual component being abolished by Cd(2+) (0.1 mM). From these results, the following hypotheses could be drawn. (1). The distribution of P/Q- and N-type channels at a single bouton is nonuniform. (2. When a focal stimulation is applied to a single bouton, L-type channels play a significant role in a generation of an action potential which subsequently activates P/Q- and N-type channels at GABA release sites. (3). Action potentials conducted through axons in the slice preparation are sufficient to depolarize the bouton membrane, even when L-type channels are suppressed.

Afferent Pathways↗
PubMedDate not supplied

Currents in the presynaptic terminal arbors of barnacle photoreceptors.

We have described the currents flowing across the presynaptic membranes of the four median photoreceptors of the giant barnacle, Balanus nubilus, using a quasi-voltage clamp arrangement. Membrane potential, measured in the terminal region of one photoreceptor, was controlled in all four terminals by feedback current supplied through the nerve containing the photoreceptors' axons. The [Ca2+]o in the saline was reduced to decrease the Ca2+ current, enabling better voltage control, and tetraethylammonium ion (TEA, 20 mM) was added to block a fast voltage-dependent K+ conductance. Depolarizing voltage steps from the resting potential in the dark (-60 mV) evoked slow, inward Ca(2+)-dependent currents which could be blocked by Co2+, Mg2+, or Cd2+. The Ca2+ currents were followed by large outward currents that persisted for many seconds after the offset of moderate or large pulses. These tail currents increased in magnitude and duration with pulse duration and reversed at about -80 mV, consistent with previous evidence for a Ca(2+)-activated K+ conductance in this membrane. When the Ca(2+)-activated outward current was reduced to zero by increasing the [K+]o so as to set EK at -20 mV, and then stepping the voltage to this value, the step evoked a steady inward Ca2+ current. Thus, the Ca2+ current did not show voltage- or Ca(2+)-dependent inactivation. When Ba2+ was substituted for Ca2+, 500-ms depolarizing steps evoked steady inward currents but no outward currents. In any given experiment, the activation voltage of the Ca2+ or Ba2+ current did not depend on holding potential. At the barnacle photoreceptor's synapse, the postsynaptic cell adapts to maintained presynaptic voltage by a mechanism that is not understood. We conclude that neither Ca2+ current inactivation nor a shift in activation voltage with holding potential can account for this adaptation.

Adaptation, Physiological↗
PubMed1999

Activity-dependent modulation of K+ currents at presynaptic terminals of mammalian central synapses.

1. The activity-dependent regulation of presynaptic K+ currents at the CA3-CA1 synapse in the rat hippocampus was investigated during a train of evoked afferent action potentials. The waveforms of presynaptic compound action potentials (cAPs) and presynaptic Ca2+ transients ([Ca2+]pre,t) were measured with fluorescent voltage-sensitive and Ca2+-sensitive indicators in rat brain slices. 2. Under control conditions, presynaptic cAPs and the accompanying [Ca2+]pre,t displayed similar amplitudes for each stimulus, suggesting that there was no cumulative change of K+ and Ca2+ currents during the test train. However, when a subgroup of presynaptic K+ channels was blocked by a low concentration of 4-aminopyridine (4-AP, 40 microM), a significant facilitation of the [Ca2+]pre,t was observed. 3. This phenomenon was not due to a direct action of 4-AP on presynaptic Ca2+ channels, but to cumulative suppression of the K+ conductance as indicated by the corresponding change in waveforms of the cAP and presynaptic fibre volley. The observed facilitation was not an artifact by virtue of increased fibre recruitment, nor was it related to the accumulation of extracellular K+; rather, it was dependent on Ca2+ influx and stimulation frequency. The time course of recovery from facilitation was closely related to the decay of the intracellular Ca2+ concentration. 4. The facilitation was not blocked by a saturating concentration of 4-AP (8 mM) but was reduced during the application of the K+ channel blocker tetraethylammonium (TEA, 10 mM), implicating the involvement of TEA-sensitive K+ channels. Such activity-dependent suppression of presynaptic K+ conductance could lead to excessive transmitter release and might explain the hippocampal epileptiform activity that can be induced by application of 4-AP.

4-Aminopyridine↗
PubMed1995

Synapsin I deficiency results in the structural change in the presynaptic terminals in the murine nervous system.

Synapsin I is one of the major synaptic vesicle-associated proteins. Previous experiments implicated its crucial role in synaptogenesis and transmitter release. To better define the role of synapsin I in vivo, we used gene targeting to disrupt the murine synapsin I gene. Mutant mice lacking synapsin I appeared to develop normally and did not have gross anatomical abnormalities. However, when we examined the presynaptic structure of the hippocampal CA3 field in detail, we found that the sizes of mossy fiber giant terminals were significantly smaller, the number of synaptic vesicles became reduced, and the presynaptic structures altered, although the mossy fiber long-term potentiation remained intact. These results suggest significant contribution of synapsin I to the formation and maintenance of the presynaptic structure.

Animals↗
PubMed2001

Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation.

Zn(2+) is found in glutamatergic nerve terminals throughout the mammalian forebrain and has diverse extracellular and intracellular actions. The anatomical location and possible synaptic signaling role for this cation have led to the hypothesis that Zn(2+) is released from presynaptic boutons, traverses the synaptic cleft, and enters postsynaptic neurons. However, these events have not been directly observed or characterized. Here we show, using microfluorescence imaging in rat hippocampal slices, that brief trains of electrical stimulation of mossy fibers caused immediate release of Zn(2+) from synaptic terminals into the extracellular microenvironment. Release was induced across a broad range of stimulus intensities and frequencies, including those likely to induce long-term potentiation. The amount of Zn(2+) release was dependent on stimulation frequency (1-200 Hz) and intensity. Release of Zn(2+) required sodium-dependent action potentials and was dependent on extracellular Ca(2+). Once released, Zn(2+) crosses the synaptic cleft and enters postsynaptic neurons, producing increases in intracellular Zn(2+) concentration. These results indicate that, like a neurotransmitter, Zn(2+) is stored in synaptic vesicles and is released into the synaptic cleft. However, unlike conventional transmitters, it also enters postsynaptic neurons, where it may have manifold physiological functions as an intracellular second messenger.

Action Potentials↗
PubMed1975

The fine structural localization of glutamate decarboxylase in developing axonal processes and presynaptic terminals of rodent cerebellum.

The immunocytochemical localization of L-glutamate decarboxylase (GAD), the enzyme which which forms gamma-aminobutyric acid (GABA), has been studied in developing rodent cerebellum. During the first 3-4 postnatal days, GAD is distributed along non-terminal portions of axonal processes in close association with small vesicles. Some of the axonal processes emanate from profiles which resemble growth cone varicosities, and are presumed to be foliopodia which extend distally from axonal growth regions. At the end of the first postnatal week the GAD-containing axonal processes are seen to form protosynaptic contacts, and GAD is localized around synaptic vesicles and at presynaptic junctional membranes. During the second and third postnatal weeks GAD gradually becomes localized to mature synaptic terminals in association with synaptic vesicle, mitochondrial, and presynaptic junctional membranes. The results suggest that GAD is present in growing neurites in close association with small vesicles prior to the time the neurites make protosynaptic contacts, and that differentiation of these contacts results in a sequestering of GAD into synaptic terminals.

Age Factors↗
PubMed1994

Colocalization of somatostatin with GABA or glutamate in distinct afferent terminals presynaptic to the Mauthner cell.

The presence of somatostatin in afferent fibers impinging on the goldfish Mauthner (M-) cell was determined using immunohistochemical methods, combined with confocal and electron microscopy, and the relationship of this peptide with inhibitory and excitatory terminals was studied. Somatostatin-reactive boutons were present only on the distal part of the M-cell's lateral dendrite. Somatostatin immunoreactivity was observed in typical large myelinated club endings (LMCEs) corresponding to mixed (electrical and chemical) eighth nerve primary afferent fibers. The axoplasm of these fibers contained dense-core vesicles (DCVs) dispersed among round vesicles. We have made a novel finding that the excitatory transmitter glutamate is present in LMCEs. Colocalization of this amino acid with somatostatin was detected in 75% of these endings using postembedding staining with gold particles of various sizes. The other structures labeled by somatostatin antibody were found to be small vesicle boutons (SVBs), which establish symmetrical synapses and contain a population of pleiomorphic vesicles with DCVs scattered among them. Double labeling with antibodies against glutamic acid decarboxylase and GABA allowed the definition of three types of biochemically characterized terminals: [somatostatin-GABA], [GABA], and [somatostatin]. However, the occurrence of DCVs in SVBs stained for GABA alone suggests that neuropeptides other than somatostatin may also coexist with GABA in this class of boutons. The coexistence of somatostatin with both inhibitory and excitatory neurotransmitters acting on the same region of a postsynaptic cell is discussed in relation to the role postulated for this peptide in synaptic plasticity.

Afferent Pathways↗
PubMed1991

[Presynaptic terminals in the sensorimotor area of the cerebral cortex in old laboratory rats].

In male laboratory rats, Wistar strain, 2 and a half years old, quantitative morphometric analysis of synapses (type I after to Gray) from the second layer of the sensorimotor area of the neocortical region was performed. Evidence was provided of enlargement of the area of presynaptic formations, their circumference and of prolongation of the active zone of the synapse. The absolute number of agranular synaptic vesicles does not change, however, the number of vesicles per area unit declines (1 micron 2). This change was proved in all regions of the presynaptic ending. The enlargement of the area of synaptic endings is discussed in relation to possible shifts of water and electrolytes between the extracellular and intracellular space as a result of ageing of nervous tissue. The authors discuss also the passive change caused by a decrease of neuropil structures and narrowing of the extracellular space. The relative decline of the number of synaptic vesicles in the entire synapse and thus in the vicinity of the active zone is taken to be the morphological basis of a certain restriction of synaptic transmission in the sensorimotor area of the cortex in old age.

Aging↗
PubMed1987

Transmitter release from presynaptic terminals of electric organ: inhibition by the calcium channel antagonist omega Conus toxin.

Cholinergic synaptosomes from electroplax of the ray Ommata discopyge release both ATP and ACh when depolarized with high K+ concentration in the presence of Ca2+. Others have shown that the ATP and ACh are released in the molar ratio found in isolated synaptic vesicles. Thus, it is assumed that the release of ATP reflects exocytosis of synaptic vesicles, and that transmitter release can be indirectly monitored by assaying ATP release. We present further evidence for this assumption and examine the effects of presynaptic neurotoxins on this ATP release. As expected for transmitter release, we find that depolarization-evoked ATP release is supported by Sr2+ and Ba2+ and is inhibited by the Ca channel antagonists Co2+ and Mn2+. Likewise, the presynaptic toxins omega-CmTX and omega-CgTX, omega peptides from the venom of the marine snails Conus magus and Conus geographus, respectively, inhibit 80% of the depolarization-evoked ATP release. Half-maximal inhibition of ATP release occurs with approximately 0.5 microM of either toxin. The toxins' effects are reversible, and when toxin is washed away, the time dependence of recovery of release is approximately first order and half complete within 40 min with omega-CmTX and 15 min with omega-CgTX. The Ca2+ ionophore A23187 induces Ca2+-dependent ATP release from resting synaptosomes. As would be expected of a Ca channel antagonist, omega-CmTX does not affect this ionophore-induced release. Leptinotarsin-d (LPTd), a putative Ca channel agonist from the Colorado potato beetle, evokes Ca2+-dependent ATP release from resting synaptosomes. omega-CmTX does not block LPTd-evoked release of ATP, which suggests that omega-CmTX and LPTd act at different sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

The process of reinnervation in the dentate gyrus of adult rats: an ultrastructural study of changes in presynaptic terminals as a result of sprouting.

The present study was undertaken to define the ultrastructure of synapses of the crossed temporodentate pathway after they had sprouted to reinnervate the dentate gyrus following the destruction of the normal ipsilateral temporodentate pathway. The synapses of the sprouted crossed temporodentate pathway were identified at the EM level by using autoradiographic techniques and by evaluating the degeneration of the pathway following secondary lesions. Both EM autoradiography and EM degeneration revealed that the terminals of the sprouted crossed temporodentate pathway formed asymmetric synapses on spines; individual terminals appeared to make more synaptic contacts per terminal (multiple synapses) than in the case of the normal crossed pathway. In the two lesioned animals exhibiting the best labeling, labeled terminals made an average of 3.0 +/- 2.2 and 2.0 +/- 1.3 contacts per terminal. In contrast, labeled terminals in normal animals exhibited only one contact per terminal. The terminals of the sprouted pathway were also larger than those of the normal crossed pathway. The synapses of the crossed temporodentate pathway that degenerated after a secondary lesion of the entorhinal cortex exhibited both electron-lucent and electron-dense forms of degeneration at 2 days postlesion. In two animals that were quantitatively analyzed, the density of degenerating synaptic terminals was 281 and 218/10,000 microns2 in the terminal field of the sprouted crossed pathway. These values are much higher than in normal animals, where the density of degenerating synaptic terminals was only 2.12/10,000 microns2 at 2 days postlesion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Morphological changes in presynaptic terminals of the chick ciliary ganglion after stimulation in vivo. A stereological study showing a net loss of total membrane.

The Edinger-Westphal nucleus of one day old chicks was stimulated in vivo. This nucleus projects via the oculomotor nerve to the ciliary ganglion. The stimulation produces morphological changes in the calyciform endings located in the ciliary ganglion. There is a significant reduction of the numerical density on area of the clear and the dense core vesicles. The numerical density of the coated vesicles is low compared to that of the clear vesicles. Their density is however almost doubled by the stimulation. The vesicles, the vacuoles and the plasma membrane were quantified using stereological procedures. A net loss of total membrane was found due to the loss of organelle membrane not compensated for by an equivalent increase of the plasma membrane. These observations are discussed in terms of the theory of vesicular membrane recycling as proposed by Heuser and Reese (1973).

Animals↗
PubMed1989

Phosphoproteins localized to presynaptic terminal linked to persistence of long-term potentiation (LTP): quantitative analysis of two-dimensional gels.

Previous findings suggest: (1) that altering protein kinase C (PKC) activity alters the persistence of long-term potentiation (LTP) in the intact hippocampal formation; and (2) that PKC activity is directly correlated with persistence of LTP in vivo as measured by the in vitro phosphorylation of two major PKC substrates in adult hippocampus, protein F1 and 80k. Using quantitative analysis of two-dimensional gels, we report here two additional phosphoproteins of 72 and 55 kDa which were directly correlated to persistence of LTP induced in the intact dorsal hippocampal formation. The phosphorylation of both proteins in response to addition of different kinase stimulators was distinct from that of protein F1 and 80k. Moreover, neither protein was a substrate for exogenous PKC. The physicochemical properties of these phosphoproteins suggest they are identical to the previously described synaptic vesicle proteins IIIa and IIIb, and as such are immunologically indistinguishable. Because proteins IIIa and IIIb are known to be phosphorylated by a Ca2+/calmodulin (CaM)-stimulated kinase, and protein F1 is known to be a plasma membrane-associated protein (P-57) which releases bound CaM in response to phosphorylation by PKC, the present findings suggest a potential mechanism in which PKC-mediated changes in plasma membrane proteins produce CaM kinase-mediated changes in synaptic vesicle proteins through a phosphorylation cascade. These membrane/vesicle alterations are postulated to underlie the increased synaptic efficacy which marks persistent LTP.

Adaptation, Physiological↗