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PubMed1980

Postnatal development of presynaptic terminals in the gigantocellular tegmental field (FTG) of the rat.

Presynaptic boutons of the gigantocellular tegmental field (FTG) of the brain stem reticular formation were analyzed by sterological techniques for changes in numerical and volumetric density during early postnatal development. Electron microscopic analysis revealed that presynaptic boutons increased in numerical density and volumetric fraction during the first 15 postnatal days. By day 15, the presynaptic boutons had reached the numerical density and volumetric fraction seen in the adult tissue. Myelination was not evident ultil day 10 and by day 30 contributed over 45% to the total volume of the FTG tissue. Presynaptic boutons were differentiated into those with spherical vesicles and those with predominantly polymorphic (i.e. oblong) vesicles. Both types of presynaptic boutons were present at day 1, but over the next 30 days the percentage of boutons with polymorphic vesicles increased to over 40%. These results revealed that the FTG region of the rat demonstrates its synaptogenic period during the earliest postnatal days. The differentiation of the synapse into two types within the FTG region suggests a morphological basis for alterations in function during early maturation.

Aging↗
PubMed2006

GABA transporters regulate a standing GABAC receptor-mediated current at a retinal presynaptic terminal.

At the axon terminal of goldfish retinal bipolar cells, GABA(C) receptors have been shown to mediate inhibitory reciprocal synaptic currents. Here, we demonstrate a novel standing GABAergic current mediated exclusively by GABA(C) receptors. Selective inhibition of GAT-1 GABA transporters on amacrine cells increases this tonic current and reveals a specific functional coupling between GAT-1 transporters and GABA(C) receptors. We propose that this GABA(C) receptor-mediated standing current serves to regulate synaptic gain by shunting depolarizing potentials that can produce Ca2+-dependent action potentials at the bipolar cell terminal. Furthermore, we find that the amount of GABA(C) receptor-mediated reciprocal feedback between bipolar cell terminals and amacrine cells is greatly increased when GAT-1 transporters are specifically blocked by NO-711 (1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride). The involvement of GAT-1 transporters in regulating this standing (or tonic) GABA(C) current implicates them in a novel role as major determinants of presynaptic excitability.

Action Potentials↗
PubMed2006

Transmitter release face Ca2+ channel clusters persist at isolated presynaptic terminals.

Ca(2+) influx through N-type Ca(2+) channels (CaV2.2) is known to be critical for transmitter release at many synapses. These channels are known to be localized to transmitter release sites, but their anchoring mechanism remains unknown. Recent studies have demonstrated that presynaptic organization is subject to interactions with the postsynaptic cell or the intervening extracellular matrix. We used a previously described high-affinity antibody against the N-type Ca(2+) channels, Ab571, to localize Ca(2+) channel clusters at the release face of an isolated giant calyx-type synapse to test whether the maintenance of these clusters requires an intact extracellular matrix or contact with the postsynaptic cell. Because the number of Ca(2+) channel clusters was unchanged after extracellular matrix dispersal or nerve terminal isolation, we conclude that presynaptic transmitter release face Ca(2+) clusters can be maintained independently of extracellular influences. Our results suggest that a presynaptic molecular scaffold is responsible for the maintenance of release site Ca(2+) channel clusters.

Animals↗
PubMed2006

Astrocyte reactivity influences the number of presynaptic terminals apposed to spinal motoneurons after axotomy.

Although synaptic plasticity is a widespread phenomenon, the underlying mechanisms leading to its occurrence are virtually unknown. In this sense, glial cells, especially astrocytes, may have a role in network changes of the nervous system, influencing the retraction of boutons as well as providing a proper perisynaptic environment, thereby affecting the replacement of inputs. Interestingly, the glial reaction does vary between strains of rats and mice. In this sense, we present evidence that C57BL/6J and A/J isogenic mice present different astrocyte reactivity after a peripheral lesion in vivo as well as in vitro, by analyzing primary cell cultures. Such a difference in the glial reaction has a direct influence on in vivo number of pre-synaptic terminals and on in vitro synaptogenesis.

Animals↗
PubMed1996

Kappa opioid receptor-like immunoreactivity in guinea pig brain: ultrastructural localization in presynaptic terminals in hippocampal formation.

Physiological and pharmacological studies have suggested that kappa opioid receptors (KORs) may be located presynaptically in the guinea pig hippocampal formation. In the present study, KOR-like immunoreactivity (-LI) was examined by using a rabbit antibody raised against a synthetic peptide from the carboxyl terminus of a cloned rat kappa receptor (KT). The specificity of affinity-purified KT antibody was confirmed by Western blotting, enzyme-linked immunosorbent assay, immunolabeling of KORs expressed in Xenopus oocytes, and immunocytochemical preadsorption controls. Specificity also was demonstrated by the light microscopic distribution of KT-LI in sections through the forebrain and the pons, which was largely consistent with the distribution of KORs previously reported, and resembled that of immunoreactivity for dynorphin B, an endogenous ligand for KORs. Detailed analysis of the hippocampal formation revealed that KT-LI was located predominantly in thin processes in the granule cell and inner molecular layers of the dentate gyrus. A few KT-labeled processes were also present in stratum lacunosum-moleculare of the CA1 region and all layers of the CA3 region of the hippocampus. By electron microscopy, KT-LI was restricted to unmyelinated axons and axon terminals, and was associated with plasma membranes, large dense-core vesicles, and cytoplasmic surfaces of small vesicles. In the dentate gyrus, immunolabeled terminals formed asymmetric synapses with granule cell perikarya and large unlabeled dendrites. In the CA3 region of hippocampus, KT-LI was present in small unmyelinated axons. The results of this study 1) demonstrate the specificity of the KT antibody, 2) show that the distribution of KT labeling corresponds well with previous KOR and dynorphin localization in many regions, and 3) provide ultrastructural evidence that KORs are located presynaptically in the guinea pig hippocampal formation.

Animals↗
PubMed2005

An Aplysia type 4 phosphodiesterase homolog localizes at the presynaptic terminals of Aplysia neuron and regulates synaptic facilitation.

The cAMP-dependent signaling pathway is critically involved in memory-related synaptic plasticity. cAMP-specific type 4 phosphodiesterases (PDE4) play a role in this process by regulating the cAMP concentration. However, it is unclear how PDE4 is involved in regulating synaptic plasticity. To address this issue in Aplysia sensory-to-motor synapses, we identified a long isoform of the PDE4 homolog in Aplysia kurodai (apPDE), with genetic and biochemical properties similar to those of mammalian PDE4s. Furthermore, apPDE is localized to the membrane and presynaptic region. Both apPDE overexpression and knock-down impaired short- and long-term facilitation, indicating that an appropriate expression level of apPDE in synaptic regions is required for normal synaptic facilitation. By using fluorescence resonance energy transfer-based measurement of in vivo protein kinase A (PKA) activation, we found that the PKA activation by 5-hydroxytryptamine (5-HT) was impaired in both apPDE-overexpressed and knock-down synapses. Analogous to the inhibition of apPDE by RNA interference, chronic rolipram treatment before 5-HT stimulation also impaired the PKA activation by 5-HT, suggesting that regulation of the synaptic cAMP level by PDE4 is critical for normal synaptic facilitation. Together, we suggest that PDE4s localized in the synapses play a critical role in regulating the optimum cAMP level required for normal synaptic plasticity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Ca(2+)-dependent Cl- current at the presynaptic terminals of goldfish retinal bipolar cells.

In ON-type bipolar cells dissociated from the goldfish retina, a slowly declining inward current (Itail) was observed after the termination of depolarizing voltage step commands, during which a Ca2+ current was elicited. The properties of Itail were investigated under the whole-cell voltage clamp. Introduction of the membrane permeant Ca2+ chelator, BAPTA/AM, into the cell suppressed Itail, indicating that Itail was activated by the increase of intracellular free Ca2+ concentration ([Ca2+]i). The major component of Itail was identified as the Ca(2+)-dependent Cl- current (ICl(Ca)), since the reversal potential of Itail was almost identical to the Cl- equilibrium potential at various extracellular Cl- concentrations ([Cl-]o). The contribution of the Na+/Ca2+ exchanger current to Itail was very small. ICl(Ca) was partially suppressed by 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) when it was locally applied to the axon terminal but not to the cell body region, suggesting that Ca(2+)-dependent Cl- channels were localized to the axon terminal. The relationship between the peak amplitude of ICl(Ca) and the amount of charge carried by the Ca2+ current was almost linear at levels less than ca. 50 pC, but became saturated at a higher Ca2+ charge.

Animals↗
PubMed2000

Interplay between facilitation, depression, and residual calcium at three presynaptic terminals.

Synapses display remarkable alterations in strength during repetitive use. Different types of synapses exhibit distinctive synaptic plasticity, but the factors giving rise to such diversity are not fully understood. To provide the experimental basis for a general model of short-term plasticity, we studied three synapses in rat brain slices at 34 degrees C: the climbing fiber to Purkinje cell synapse, the parallel fiber to Purkinje cell synapse, and the Schaffer collateral to CA1 pyramidal cell synapse. These synapses exhibited a broad range of responses to regular and Poisson stimulus trains. Depression dominated at the climbing fiber synapse, facilitation was prominent at the parallel fiber synapse, and both depression and facilitation were apparent in the Schaffer collateral synapse. These synapses were modeled by incorporating mechanisms of short-term plasticity that are known to be driven by residual presynaptic calcium (Ca(res)). In our model, release is the product of two factors: facilitation and refractory depression. Facilitation is caused by a calcium-dependent increase in the probability of release. Refractory depression is a consequence of release sites becoming transiently ineffective after release. These sites recover with a time course that is accelerated by elevations of Ca(res). Facilitation and refractory depression are coupled by their common dependence on Ca(res) and because increased transmitter release leads to greater synaptic depression. This model captures the behavior of three different synapses for various stimulus conditions. The interplay of facilitation and depression dictates synaptic strength and variability during repetitive activation. The resulting synaptic plasticity transforms the timing of presynaptic spikes into varying postsynaptic response amplitudes.

Animals↗
PubMed2004

Distinct profiles of refilling of inhibitory neurotransmitters into presynaptic terminals projecting to spinal neurones in immature rats.

Corelease of glycine and GABA from the single synaptic terminal (synaptic bouton) is well accepted in immature rat spinal cord and brainstem. However, it raises the question of how glycine and GABA are accumulated in the same synaptic vesicles and coreleased. To address this issue, spontaneous miniature inhibitory postsynaptic currents (mIPSCs) and focally evoked IPSCs (eIPSCs) mediated via a single synapse were recorded from synaptic bouton preparations of the rat immature sacral dorsal commissural nucleus (SDCN) neurones by whole-cell patch recording. Focal stimulation of a single synaptic bouton revealed that three different quantal releases occur from a single synaptic bouton: i.e. pure glycine, pure GABA, and mixed. Prolonged treatment with bafilomycin A1, a vacuolar-type H+/ATPase inhibitor, to the SDCN neurone greatly suppressed frequency and amplitude of the mIPSCs. During washing out of bafilomycin A1, complete recovery in the amplitude of glycinergic mIPSCs was observed, while that of GABAergic and mixed mIPSCs was incomplete. These observations indicate that three types of vesicles coexist in single synaptic terminals, and that refilling of glycine into the synaptic vesicle predominantes over GABA after pretreatment with bafilomycin A1 in immature rats. This could be explained by the decrease in the cytosolic concentration of GABA, or by the presence of subtypes of vesicular inhibitory amino acid transporter in the synaptic vesicle membrane.

Animals↗
PubMed1998

Calcium current during a single action potential in a large presynaptic terminal of the rat brainstem.

1. The calcium current of a 'giant' synaptic terminal (the calyx of Held) was studied using two-electrode voltage clamp in slices of the rat brainstem. 2. In terminals with a long axon (length > 100 microns), the passive current transient decayed biexponentially following voltage steps. In terminals with a short axon (length < 30 microns), the slow component was reduced or absent. These terminals also had small slow calcium tail currents following long depolarizing voltage steps, suggesting that these are largely due to axonal calcium channels. 3. Terminals were voltage clamped with action potential waveform commands. At both 24 and 36 degrees C the calcium current began shortly after the peak of the action potential and ended before the terminal was fully repolarized. 4. The calcium current during the repolarization phase was 69 +/- 1% (n = 3) of maximal, judged from the increase in this current when a plateau phase was added to the action potential waveform. 5. A Hodgkin-Huxley m2 model, based on the measured activation and deactivation of the calcium current, reproduced both the time course and the amplitude increase of the calcium currents during the different action potential waveforms well. 6. The fast gating of the calcium channels in the terminal ensures that they are effectively opened during the repolarization phase of an action potential. This implies that the distance between open calcium channels is minimized, which is in agreement with the view that multiple calcium channels are needed to release a vesicle in this synapse.

Action Potentials↗
PubMed2004

Vesicle turnover in developing neurons: how to build a presynaptic terminal.

Over the past decade, evidence has accumulated indicating that, during development, the construction of synapses--the sites of communication between neurons--might rely on the utilization of preassembled sets of synaptic proteins, which have already accumulated in the axon and are highly mobile, before getting recruited to the sites of contact with the postsynaptic neuron. In this review, we discuss evidence from most recent publications pointing to the existence of active vesicle traffic and turnover in developing neurons, which lead to the construction of new synaptic sites.

Animals↗
PubMed1996

Adaptation of Ca(2+)-triggered exocytosis in presynaptic terminals.

Rapid increases in Ca2+ concentration, produced by photolysis of caged Ca2+, triggered exocytosis in squid nerve terminals. This exocytosis was transient in nature, decaying with a time constant of approximately 30 ms. The decay could not be explained by a decline in presynaptic Ca2+ concentration, depletion of synaptic vesicles, or desensitization of postsynaptic receptors. Experiments in which Ca2+ was increased either in a series of steps or continuously at different rates suggested that the decay is caused by adaptation of the exocytotic Ca2+ receptor to higher levels of Ca2+. This adjustable sensitivity to Ca2+ represents a novel property of the triggering mechanism that can be used to evaluate molecular models of exocytosis. Adaptation can limit the amount of transmitter released by a nerve terminal and permit the speed of a presynaptic Ca2+ rise to serve as a critical determinant of synaptic efficacy.

Adaptation, Physiological↗
PubMed2004

Fast endocytosis is inhibited by GABA-mediated chloride influx at a presynaptic terminal.

Although multiple kinetic components of synaptic vesicle endocytosis have been identified, it has remained unclear whether neurons can differentially modulate these components. Using membrane capacitance measurements from isolated goldfish bipolar cell terminals, we found that the kinetics of endocytosis in retinal slices (single exponential decay; tau > 10 s) were significantly slower than those in acutely dissociated terminals (double exponential decay; tau(fast) approximately 1-2 s; tau(slow) > 10 s). Surprisingly, GABA(A) and/or GABA(C) receptor antagonists restored the fast component of endocytosis to terminals in retinal slices. Blocking GABAergic feedback from reciprocal synapses or removing external Cl(-) ions also allowed for fast endocytosis. Elevating internal Cl(-) via the patch pipette invariably slowed endocytosis, even in terminals dialyzed with increased Ca(2+) buffer. These results suggest a new role for GABA and Cl(-) ions in blocking the trigger for fast endocytosis at this ribbon-type synapse.

Animals↗
PubMed1995

Synaphin: a protein associated with the docking/fusion complex in presynaptic terminals.

We previously identified a 19 kDa protein associated with the docking/fusion complex involved in neurotransmitter release. A cDNA for this protein was cloned from a bovine brain cDNA library using an oligonucleotide probe based on its partial amino acid sequence. The protein (named synaphin) encoded by the cDNA is a very hydrophilic protein rich in glutamic acid and lysine residues. It lacks any putative transmembrane segments or strongly hydrophobic domains. Immunoblots with antibodies against synaphin detected the protein only in the nervous system among the tissues examined. In brain, it exists mainly in the soluble fraction and is scarce in synaptic vesicles.

Adaptor Proteins, Vesicular Transport↗
PubMed1994

Nicotine increases [Ca2+]i in rat sublingual mucous acini by stimulating neurotransmitter release from presynaptic terminals.

The effects of nicotine on the intracellular free Ca2+ concentration ([Ca2+]i) were examined using the Ca(2+)-sensitive fluorescent dyes indo-1 and fura-2 in isolated rat sublingual mucous acini. Nicotine induced a dose-dependent increase in [Ca2+]i. In contrast to the muscarinic agonist carbachol-induced rise in [Ca2+]i, the nicotine-stimulated increase was abolished in a Ca(2+)-free medium, in the presence of L-type Ca2+ channel blockers (diltiazem and D888), by depolarization (high extracellular K+), and if the intracellular Ca2+ pool was first depleted with thapsigargin, an endoplasmic Ca(2+)-ATPase inhibitor. Furthermore, inhibitors of the nicotine acetylcholine receptor (mecamylamine, decamethonium, hexamethonium, tubocurarine, and alpha-bungarotoxin) blocked the nicotine-stimulated increase in [Ca2+]i without affecting the muscarinic-stimulated [Ca2+]i increase, whereas, muscarinic antagonists (atropine, pirenzepine and 4-diphenylacetoxy-N-methylpiperidine methiodide [4-DAMP]) inhibited both the nicotine- and carbachol-induced [Ca2+]i increases. Nicotine stimulation increased inositol 1,4,5-trisphosphate (IP3) content by 50%. Inhibition of the IP3-sensitive intracellular Ca2+ release pathway with 8-(diethylamino)-ocytl-3,4,5-trimethoxybenzoate (TMB-8) prevented the nicotine-induced increase in [Ca2+]i. Confocal imaging of [Ca2+]i indicated that the nicotine-induced and the carbachol-induced increases in [Ca2+]i occurred in the same cells within an acinus. However, in single sublingual acinar cells nicotine did not increase [Ca2+]i, whereas, carbachol did. Taken together, these results suggest that nicotine first triggers the release of acetylcholine from presynaptic nerve terminals associated with the dispersed sublingual acini which then activates muscarinic receptors.

Acetylcholine↗
PubMed2001

Uncoating of clathrin-coated vesicles in presynaptic terminals: roles for Hsc70 and auxilin.

We have examined the roles of Hsc70 and auxilin in the uncoating of clathrin-coated vesicles (CCVs) during neuronal endocytosis. We identified two peptides that inhibit the ability of Hsc70 and auxilin to uncoat CCVs in vitro. When injected into nerve terminals, these peptides inhibited both synaptic transmission and CCV uncoating. Mutation of a conserved HPD motif within the J domain of auxilin prevented binding to Hsc70 in vitro and injecting this mutant protein inhibited CCV uncoating in vivo, demonstrating that the interaction of auxilin with Hsc70 is critical for CCV uncoating. These studies establish that auxilin and Hsc70 participate in synaptic vesicle recycling in neurons and that an interaction between these proteins is required for CCV uncoating.

Adaptor Proteins, Vesicular Transport↗
PubMed1997

Presynaptic terminals in hyaline cells of normal and overstimulated chick inner ears.

Hyaline cells are non-sensory epithelial cells of the vibrating part of the basilar membrane of chicks; they receive an extensive efferent innervation. Although these anatomical features suggest roles in auditory transduction, very little is known about the function of these cells. One possible way to understand function is by lesion experiments. We used synapsin-specific antibodies to study changes that occur in the pattern of efferent innervation in hyaline cells after lesion of the sensory epithelium induced by acoustic overstimulation. We found only small changes in hyaline cells after such trauma. These included a small increase in size and a small decrease in density of nerve terminals on hyaline cells. This suggests that hyaline cells and their nerve terminals are less susceptible to acoustic trauma than hair cells. Using neurofilament-specific antibodies we found little or no trauma-induced change in the density of nerve fibres that cross the basilar papilla and reach the hyaline cell region. This finding suggested that trauma to the hair cells does not necessarily lead to changes in the efferent fibres that cross the papilla and extend into the hyaline cell region. Using the trauma and the morphological parameters studied here, it appears that a moderate lesion in the hair cell region in the avian inner ear does not influence the hyaline cells or their innervation.

Acoustic Stimulation↗
PubMed2004

Ca2+ influx through distinct routes controls exocytosis and endocytosis at drosophila presynaptic terminals.

Endocytosis of synaptic vesicles follows exocytosis, and both processes require external Ca(2+). However, it is not known whether Ca(2+) influx through one route initiates both processes. At larval Drosophila neuromuscular junctions, we separately measured exocytosis and endocytosis using FM1-43. In a temperature-sensitive Ca(2+) channel mutant, cacophony(TS2), exocytosis induced by high K(+) decreased at nonpermissive temperatures, while endocytosis remained unchanged. In wild-type larvae, a spider toxin, PLTXII, preferentially inhibited exocytosis, whereas the Ca(2+) channel blockers flunarizine and La(3+) selectively depressed endocytosis. None of these blockers affected exocytosis or endocytosis induced by a Ca(2+) ionophore. Evoked synaptic potentials were depressed regardless of stimulus frequency in cacophony(TS2) at nonpermissive temperatures and in wild-type by PLTXII, whereas flunarizine or La(3+) gradually depressed synaptic potentials only during high-frequency stimulation, suggesting depletion of synaptic vesicles due to blockade of endocytosis. In shibire(ts1), a dynamin mutant, flunarizine or La(3+) inhibited assembly of clathrin at the plasma membrane during stimulation without affecting dynamin function.

Animals↗