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PubMed1979

Development of ocularity domains and growth behaviour of axon terminals.

Ontogenetic development of ocularity domains--stripes, patches and layers in cortex, colliculus superior and lateral geniculate nucleus--is the result of organization that may either be intrinsic to the postsynaptic structure or induced to it by the afferents. A specific type of axonal growth behaviour that was recently proposed as a basis for ontogenetic development of retinotopy is sufficient to account also for ocularity domains. No intrinsic organization in the postsynaptic structure is required. The latter merely serves as a propagating medium for markers carried by the presynaptic terminals. Computer simulations demonstrate the mechanism to be complete and consistent.

Animals↗
PubMed1985

A transient increase in the activity of CA3 neurons induces a long-lasting reduction in the excitability of Schaffer collateral terminals in rat hippocampus.

Following high frequency discharges of CA3 neurons, a long-lasting potentiation (LLP) of the CA1 neuronal population spike results. Subsequent to a transient increase in the firing rate of CA3 neurons produced by the application of DL-homocysteate on the soma in the presence of normal medium but not in the presence of Ca2+ -free (Mn2+ -containing) medium, the threshold for antidromic activation in the CA1 area of the neuron was increased for a prolonged period of time. Since the induction of the presynaptic terminal excitability reduction as well as LLP of the CA1 population spike are Ca2+ -dependent, a cause-and-effect relationship may exist between these two processes.

Animals↗
PubMed1984

Retinal terminals in the goldfish optic tectum: identification and characterization.

Retinal terminal profiles in the goldfish optic tectum were identified electron microscopically after (1) labeling with horseradish peroxidase and (2) in the early stages of degeneration in short-term eye enucleates. All labeled terminals shared certain common morphological characteristics which were identical to those of a population of terminals in normal tecta. Terminals of this type disappeared 30 days after enucleation of the contralateral eye. Retinal terminal presynaptic profiles were characterized by (1) round and oval synaptic vesicles; (2) mitochondria with irregular, randomly oriented cristae, large intracristal spaces, dilated membrane spaces, and primarily light matrices; (3) a wide range in profile area, 0.06-6.82 micrometers2; (4) large numbers of synaptic vesicles per profile area (168 +/- 33 synaptic vesicles per micrometers2; (5) asymmetric synapses; and (6) multiple synaptic contacts (1.46 +/- 0.73 per terminal profile). The postsynaptic elements included both dendritic and, less commonly, pleomorphic vesicle-containing profiles. The majority of postsynaptic dendritic profiles were small (0.01-0.40 micrometers2). Serial synaptic contacts were occasionally seen. The combination of vesicular and mitochondrial morphology (1 and 2 above) was necessary and sufficient to establish the retinal origin of a terminal, but use of such criteria would underestimate the number of retinotectal terminals by omitting those which did not have a mitochondrion in the plane of section. The number of such terminals was calculated from independent measurements, and the total number of retinal terminal profiles per area of neuropil was estimated.

Animals↗
PubMed1980

The morphology of synaptic profiles in explants of foetal and neonatal mouse cerebral cortex maintained in a magnesium-enriched environment.

The present study examines the ultrastructure of synaptic profiles developed in explant cultures of immature mouse cerebral cortex, maintained for prolonged periods in a magnesium-rich environment. The ethanolic phosphotungstic acid method was employed in addition to conventional preparation procedures so that paramembranous densities could be clearly observed. Although presynaptic terminals were frequently packed to capacity with vesicles in cultures maintained in magnesium-rich media, there was always a proportion which contained loosely collected vesicles. Few other changes in synaptic morphology were apparent and the paramembranous densities were unaffected. The reasons for the effectiveness of the transmission block, the absence of any change in the morphology of paramembranous densities, and the excessive crowding of presynaptic vesicles are considered and discussed.

Animals↗
PubMed2004

Endocannabinoid-independent retrograde signaling at inhibitory synapses in layer 2/3 of neocortex: involvement of vesicular glutamate transporter 3.

Recent studies implicate dendritic endocannabinoid release from subsynaptic dendrites and subsequent inhibition of neurotransmitter release from nerve terminals as a means of retrograde signaling in multiple brain regions. Here we show that type 1 cannabinoid receptor-mediated endocannabinoid signaling is not involved in the retrograde control of synaptic efficacy at inhibitory synapses between fast-spiking interneurons and pyramidal cells in layer 2/3 of the neocortex. Vesicular neurotransmitter transporters, such as vesicular glutamate transporters (VGLUTs) 1 and 2, are localized to presynaptic terminals and accumulate neurotransmitters into synaptic vesicles. A third subtype of VGLUTs (VGLUT3) was recently identified and found localized to dendrites of various cell types. We demonstrate, using multiple immunofluorescence labeling and confocal laser-scanning microscopy, that VGLUT3-like immunoreactivity is present in dendrites of layer 2/3 pyramidal neurons in the rat neocortex. Electron microscopy analysis confirmed that VGLUT3-like labeling is localized to vesicular structures, which show a tendency to accumulate in close proximity to postsynaptic specializations in dendritic shafts of pyramidal cells. Dual whole-cell recordings revealed that retrograde signaling between fast-spiking interneurons and pyramidal cells was enhanced under conditions of maximal efficacy of VGLUT3-mediated glutamate uptake, whereas it was reduced when glutamate uptake was inhibited by incrementing concentrations of the nonselective VGLUT inhibitor Evans blue (0.5-5.0 microm) or intracellular Cl- concentrations (4-145 mm). Our results present further evidence that dendritic vesicular glutamate release, controlled by novel VGLUT isoforms, provides fast negative feedback at inhibitory neocortical synapses, and demonstrate that glutamate can act as a retrograde messenger in the CNS.

Amino Acid Transport Systems, Acidic↗
PubMed1986

Synaptic connections of cholecystokinin-immunoreactive neurons and terminals in the rat fascia dentata: a combined light and electron microscopic study.

We report here on the fine structure and synaptic connections of neurons and axon terminals in the rat fascia dentata displaying immunoreactivity to antibodies against cholecystokinin octapeptide (CCK). In the fascia dentata and hilar region, CCK-immunoreactivity was confined to nonpyramidal neurons that were similar in appearance to basket cells known to use gamma-aminobutyric acid (GABA) as neurotransmitter. These neurons exhibited dense accumulations of endoplasmic reticulum and infolded nuclei, and established asymmetric and symmetric synaptic contacts with presynaptic terminals. Among those terminals that formed asymmetric synaptic contacts, giant mossy fiber boutons arising from granule cell axons were identified. Cholecystokinin-immunoreactive terminals established symmetric synaptic contacts on the cell bodies and dendrites of granule cells. Similar contacts were formed on nonimmunoreactive hilar neurons. Some of these hilar cells were identified as commissural neurons by retrograde filling with horseradish peroxidase (HRP) following injection of the tracer into the contralateral fascia dentata. Synaptic contacts were rarely observed between immunolabeled pre- and postsynaptic elements. The results are discussed with regard to inhibitory processes in the fascia dentata since other studies have shown that CCK is coexistent with GABA in hippocampal nonpyramidal neurons.

Animals↗
PubMed1997

Decreased probability of neurotransmitter release underlies striatal long-term depression and postnatal development of corticostriatal synapses.

Changes in synaptic efficacy are crucial for the development of appropriate neural circuits and brain information storage. We have investigated mechanisms underlying long-term depression (LTD) at glutamatergic synapses in the striatum, a brain region important in motor performance and cognition, and a target for Huntington and Parkinson diseases. Induction of striatal LTD is dependent on postsynaptic depolarization and calcium influx through L-type channels. Surprisingly, LTD maintenance appears to involve a decrease in the probability of neurotransmitter release from presynaptic terminals as evidenced by increases in paired-pulse facilitation and the coefficient of variation of synaptic responses that are tightly associated with LTD expression. Furthermore, both the apparent probability of neurotransmitter release and the magnitude of LTD decrease concomitantly during postnatal development, consistent with the idea that striatal LTD is involved in a developmental decrease in the probability of neurotransmitter release at corticostriatal synapses. The presynaptic changes that underlie striatal LTD may also be important for motor performance and certain forms of learning and memory.

Aging↗
PubMed1999

Nicotinic modulation of glutamate and GABA synaptic transmission of hippocampal neurons.

Although the hippocampus expresses nicotinic acetylcholine receptors (nAChRs) and receives cholinergic innervation, the functional roles of these receptors are not completely understood. Our results indicated that presynaptic nAChRs mediated a calcium influx that enhanced the release of both glutamate and GABA. Fura-2 detection of calcium in single mossy fiber presynaptic terminals indicated that nAChRs directly mediated a calcium influx. In hippocampal neurons in primary culture, both spontaneous vesicular release and evoked release of glutamate and GABA were enhanced by nicotine. The nicotinic current displayed rapid desensitization kinetics, and the response to nicotine was inhibited by alpha-bungarotoxin and methyllcaconitine, suggesting that nAChRs containing the alpha 7 subunit mediated the effect. Modulation of synaptic activity by presynaptic calcium influx may represent a physiological role of acetylcholine in the brain, as well as a mechanism of action of nicotine.

Acetylcholine↗
PubMed2006

Regional alpha-synuclein aggregation, dopaminergic dysregulation, and the development of drug-related visual hallucinations in Parkinson's disease.

Visual hallucinations in Parkinson's disease are usually treatment-related and occur in at least 30% of patients. Although their clinical and epidemiological features have been extensively reviewed, their etiopathogenesis remains a matter of debate. Based on the current evidence available, this review suggests that regional neurodegeneration of the ventral dopaminergic pathway, as evident in the aggregation of the protein alpha-synuclein, is the main event linked to the development of visual hallucinations in Parkinson's disease. Denervation supersensitivity of dopaminergic receptors in ventral striatal and mesocorticolimbic areas as well as defective synaptic buffering ability due to the loss of dopaminergic presynaptic terminals and dopamine transporter may be among the key factors leading to visual hallucinations in Parkinson's disease.

Antiparkinson Agents↗
PubMed2006

Synaptic depression and short-term habituation are located in the sensory part of the mammalian startle pathway.

BACKGROUND: Short-term habituation of the startle response represents an elementary form of learning in mammals. The underlying mechanism is located within the primary startle pathway, presumably at sensory synapses on giant neurons in the caudal pontine reticular nucleus (PnC). Short trains of action potentials in sensory afferent fibers induce depression of synaptic responses in PnC giant neurons, a phenomenon that has been proposed to be the cellular correlate for short-term habituation. We address here the question whether both this synaptic depression and the short-term habituation of the startle response are localized at the presynaptic terminals of sensory afferents. If this is confirmed, it would imply that these processes take place prior to multimodal signal integration, rather than occurring at postsynaptic sites on PnC giant neurons that directly drive motor neurons. RESULTS: Patch-clamp recordings in vitro were combined with behavioral experiments; synaptic depression was specific for the input pathway stimulated and did not affect signals elicited by other sensory afferents. Concordant with this, short-term habituation of the acoustic startle response in behavioral experiments did not influence tactile startle response amplitudes and vice versa. Further electrophysiological analysis showed that the passive properties of the postsynaptic neuron were unchanged but revealed some alterations in short-term plasticity during depression. Moreover, depression was induced only by trains of presynaptic action potentials and not by single pulses. There was no evidence for transmitter receptor desensitization. In summary, the data indicates that the synaptic depression mechanism is located presynaptically. CONCLUSION: Our electrophysiological and behavioral data strongly indicate that synaptic depression in the PnC as well as short-term habituation are located in the sensory part of the startle pathway, namely at the axon terminals of sensory afferents in the PnC. Our results further corroborate the link between synaptic depression and short-term habituation of the startle response.

Acoustic Stimulation↗
PubMed1997

Study of the inhibitor of the crayfish neuromuscular junction by presynaptic voltage control.

The inhibitor of the crayfish opener muscle was investigated by a presynaptic voltage control method. Two microelectrodes were inserted into the inhibitor and the amplitude and duration of presynaptic depolarization were controlled by a voltage-clamp amplifier. The inhibitory postsynaptic potential (IPSP) was measured from a muscle fiber located near the presynaptic voltage electrode. Nonlinear summation of IPSP amplitudes was corrected after chloride equilibrium potential was measured. With the use of 5-ms presynaptic pulses, the depolarization-release coupling (D-R) curve constructed from IPSP peak amplitudes (IPSPcor) had a threshold of about -35 mV and reached its maximal level at -5 to -10 mV. Depolarization beyond the maximum led to a suppression of neurotransmitter release. When transmitter release during a presynaptic pulse was completely suppressed, IPSPs activated by tail current could be identified with an average synaptic delay of 2.5 ms. Transmitter secretion triggered by a calcium current activated during the 5-ms pulses (IPSPon) was also measured on the rising phase of an IPSP, at 2.5 ms after the end of the 5-ms pulses. D-R coupling plots measured from IPSPon exhibited a more pronounced suppression than that obtained from IPSPcor. The effect of presynaptic pulse duration on the level of transmitter release was analyzed. Transmitter release increased with increasing duration and was nearly saturated by 20-ms pulses depolarized to 0 mV. The following conditions were identified as necessary to obtain a consistent D-R curve with a clear suppression: 1) small animals, 3.8 cm head to tail, 2) 15 degrees C, 3) 40 mM tetraethylammonium and 1 mM 4-aminopyridine, 4) an extracellular calcium concentration of < or = 10 mM. In addition, a consistent correlation was found among the branching pattern of the inhibitor, the placement of the presynaptic electrode, and the characteristics of the D-R curves. An ideal presynaptic electrode configuration involved placing the voltage electrode in a secondary branch, approximately 100 microns from the main branch point, and placing the current electrode at the branch point. Postsynaptically, optimal recordings were obtained from muscle fibers innervated by a single branch of the inhibitor that originated from a point near the presynaptic voltage electrode. A cable-release model was constructed to evaluate the relationship between the shape of the D-R coupling curves and the space constants of the presynaptic terminals. A comparison between the model and the D-R coupling curves suggested that the space constant of an inhibitor branch on a muscle fiber is > or = 8 times longer than its actual length. Therefore the upper limit estimate of the space constant of a typical preparation is approximately 3 mm. Results reported here outline morphological and physiological conditions needed to achieve optimal control of the presynaptic branch of the crayfish inhibitor. The cable-release model quantitatively defines the extent of presynaptic voltage control.

Animals↗
PubMed2000

In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease.

Clinical symptoms of Parkinson's disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptomatic threshold. To explore the mechanisms of functional compensation that occur in presynaptic DA nerve terminals in PD, we compared striatal positron emission tomographic (PET) measurements by using [11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were performed in three-dimensional mode by using each tracer on 35 patients and 16 age-matched, normal controls. PET measurements by the three tracers were compared between subgroups of earlier and later stages of PD, between drug-naive and drug-treated subgroups of PD, and between subregions of the parkinsonian striatum. The quantitative relationships of [18F]dopa and [11]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD and the normal control subjects. We found that [18F]dopa Ki was reduced less than the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum, whereas the [11C]methylphenidate binding potential was reduced more than [11C]DTBZ binding potential. These observations suggest that the activity of aromatic L-amino acid decarboxylase is up-regulated, whereas the plasma membrane DA transporter is down-regulated in the striatum of patients with PD.

Aged↗
PubMed1988

Local synaptic organization of cholinergic neurons in the basolateral hypothalamus.

A monoclonal antibody to choline acetyltransferase (ChAT) was utilized for immunocytochemical identification of cholinergic neurons in the basolateral hypothalamus. Light and electron microscopic examination revealed a network of cell bodies, dendrites, and axonal processes dorsolateral to the supraoptic nucleus. Within this region the cells immunoreactive for ChAT receive numerous unlabeled terminals which contact dendrites, cell soma, axons and occasional somatic spines. In a few cases, small ChAT-immunoreactive terminals were observed contacting a cholinergic cell soma or large dendrite. Many ChAT-immunoreactive fibers were directed toward the supraoptic nucleus forming a dense local network but very few of these fibers penetrated deeper than approximately 20 micron into the supraoptic nucleus. A total of 63 ChAT-immunoreactive terminals were mapped within the basal hypothalamus, of which the vast majority contacted unlabeled dendrites immediately dorsolateral to the supraoptic nucleus. Labeled terminals were rare or nonexistent in the medial portions of the hypothalamus or deep within the supraoptic nucleus. This pattern of ChAT terminal densities correlates with the distribution of binding for the muscarinic cholinergic probe, [3H]quinuclidinylbenzilate, but not the binding of the putative nicotinic cholinergic probe, [125I]alpha-bungarotoxin, which is high within the supraoptic nucleus. Thus, the cholinergic neurons of the basal hypothalamus appear to form a network of intrinsic connections which probably represent input to muscarinic cholinergic receptors. No evidence was found to suggest that cholinergic presynaptic terminals were colocalized with the alpha-bungarotoxin binding protein within the supraoptic nucleus.

Animals↗
PubMed1987

Synaptic organization of the nucleus of the optic tract in the rabbit: a combined Golgi-electron microscopic study.

The organization of the nucleus of the optic tract was investigated with light and electron microscopy in combination with Golgi impregnation. In Golgi material, neurons ranged in size from 10 to 25 microns with three to seven principal dendrites extending predominantly parallel to the fibres of the optic tract, irrespective of their location within the nucleus. In some areas dendrites extended into the neuropil of the adjacent dorsal terminal nucleus of the accessory optic system and the posterior pretectal nucleus. Occasionally spines and appendages were observed. The fine structure of the nuclei, perikarya and the dendritic arborization did not allow a well-defined distinction between interneurons and projection neurons. The synaptic organization of the nucleus of the optic tract showed great resemblance to the neuropil of the lateral geniculate nucleus and the superior colliculus. Similar types of presynaptic terminals were noticed: (i) R-terminals were either large and scalloped or small and regular in outline with spherical vesicles and electron-lucent mitochondria, and showed asymmetric contact zones; (ii) F-terminals with flattened vesicles, opaque mitochondria and symmetric contact zones; (iii) RLD-terminals with spherical vesicles and electron-dense mitochondria and asymmetric contact zones; (iv) P-terminals with pleomorphic vesicles and electron-lucent or opaque mitochondria and asymmetric synaptic thickenings. These different types of terminal were found isolated in the neuropil or in clusters of synapses. The most striking differences between the nucleus of the optic tract and the lateral geniculate nucleus were the relative scarcity of F-terminals in the clusters, the paucity of triadic arrangements and the relatively small size of the R-terminals. The differences in ultrastructure may be related to retinal W-type ganglion cells, which form the main retinal input to the nucleus of the optic tract and could also be related to the physiologically identified direction-selective units within the nucleus of the optic tract.

Animals↗
PubMed1987

Reorganization of the projection from the sensory cortex to the motor cortex following elimination of the thalamic projection to the motor cortex in cats; Golgi, electron microscope and degeneration study.

Changes of terminal connections of projection fibers from area 2 of the sensory cortex to the motor cortex following chronic lesion in the thalamus were examined using the electron microscope. The lesioned areas included nucleus ventralis anterior, n. ventralis lateralis and rostral part of n. ventralis posterolateralis. The synaptic sites were identified using the Golgi impregnation method to identify postsynaptic neurons in the motor cortex and the axonal degeneration method to identify presynaptic terminals of fibers originating from area 2. The following results were obtained. (1) The number of degenerating terminals per unit area in the motor cortex was increased to nearly twice that in normal animals. (2) The number of degenerating terminals synapsing with stellate cells was not increased but stayed more or less the same as in normal animals. (3) The number of degenerating terminals contacting pyramidal cells increased substantially, to more than twice that in normal animals. (4) These newly formed synapses were found on proximal dendritic shafts of the pyramidal cells in both layers III and V, suggesting that these synapses occupied the spaces where the thalamocortical terminals were located. (5) The functional significance of these newly formed synapses was discussed in relation to the recovery of motor function following thalamic lesion.

Animals↗
PubMed1985

Differential visualization of dopamine and norepinephrine uptake sites in rat brain using [3H]mazindol autoradiography.

Mazindol is a potent inhibitor of neuronal dopamine (DA) and norepinephrine (NE) uptake. DA and NE uptake sites in rat brain have been differentially visualized using [3H]mazindol autoradiography. At appropriate concentrations, desipramine (DMI) selectively inhibits [3H]mazindol binding to NE uptake sites without significantly affecting binding to DA uptake sites. The localization of DMI-insensitive specific [3H] mazindol binding, reflecting DA uptake sites, is densest in the caudate-putamen, the nucleus accumbens, the olfactory tubercle, the subthalamic nucleus, the ventral tegmental area, the substantia nigra (SN) pars compacta, and the anterior olfactory nuclei. In contrast, the localization of DMI-sensitive specific [3H]mazindol binding, representing NE uptake sites, is densest in the locus coeruleus, the nucleus of the solitary tract, the bed nucleus of the stria terminalis, the paraventricular and periventricular nuclei of the hypothalamus, and the anteroventral thalamus. The distribution of DMI-insensitive specific [3H]mazindol binding closely parallels that of dopaminergic terminal and somatodendritic regions, while the distribution of DMI-sensitive specific [3H]mazindol binding correlates well with the regional localization of noradrenergic terminals and cell bodies. Injection of 6-hydroxydopamine, ibotenic acid, or colchicine into the SN decreases [3H]mazindol binding to DA uptake sites in the ipsilateral caudate-putamen by 85%. In contrast, ibotenic acid lesions of the caudate-putamen do not reduce [3H]mazindol binding to either the ipsilateral or contralateral caudate-putamen. Thus, the DA uptake sites in the caudate-putamen are located on the presynaptic terminals of dopaminergic axons originating from the SN.

Animals↗
PubMed1992

Three-dimensional analysis of the relationship between synaptic pathology and neuropil threads in Alzheimer disease.

Recent studies have shown that the Alzheimer disease (AD) neocortex is characterized by a loss of large neurons, the presence of dilated terminal axons, widespread loss of synapses, and a disruption of the dendritic cytoskeleton which is manifested as Tau immunoreactive threads. In the present study we have investigated the relationship between synaptic and dendritic abnormalities in the neocortex of Alzheimer patients and examined the extent to which these structural alterations correlate with the severity of cognitive impairment in AD. Quantitative neuroanatomical data were obtained from immunofluorescence-labeled specimens using a laser-scanning confocal microscope, computer-assisted image processing and serial section reconstruction techniques. We found that the AD cases showed a 34% loss in the number of presynaptic terminals per 100 square (sq) microns, many of which showed structural abnormalities. The AD neuropil had an average of 10 +/- 7 dendritic threads per 1,000 sq microns, with the average thread measuring 2 sq microns. Severe AD cases had thicker threads compared with mild to moderate AD cases. Three-dimensional analysis showed clustering of synapses around threads, as well as presynaptic boutons apposed to dendritic neuropil threads. Statistical analysis showed that the strongest correlation was between synapse density and Blessed score of cognitive impairment. Thread counts did not correlate with either but were correlated with tangle counts. Stepwise multiple regression analysis showed that tangle counts, but not threads, strengthened the correlation between Blessed score and synapses. We conclude that synaptic damage may precede dendritic thread and tangle formation, and that threads do not necessarily induce synaptic pathology. Instead, dendrite sprouting in the denervated regions could be associated with increased accumulation of cytoskeletal proteins observed in the dendritic threads.

Aged↗
PubMed1990

Facilitatory and inhibitory transmitters modulate spontaneous transmitter release at cultured Aplysia sensorimotor synapses.

1. The monoamine transmitter 5-hydroxytryptamine (5-HT) and the peptide Phe-Met-Arg-Phe-amide (FMRFa), which appear to contribute to presynaptic facilitation and inhibition of the sensorimotor synapse in the abdominal ganglion of Aplysia, can modulate the frequency of spontaneous transmitter release at synapses formed between dissociated Aplysia sensory neurones and motoneurones in vitro. 2. 5-HT caused a decrease in the mean time interval between consecutive miniature EPSPs (mEPSPs), while FMRFa, applied either by itself or together with 5-HT, caused an increase in the mean time interval between consecutive mEPSPs. 3. Depolarization of the presynaptic neurone caused a decrease in the mean time interval between consecutive mEPSPs. This modulation required external Ca2+. 4. 5-HT and FMRFa were able to modulate spontaneous release when applied in saline solutions lacking Ca2+ and containing Ca2(+)-chelating agents, suggesting that the modulation of spontaneous release by 5-HT and FMRFa did not require a Ca2+ influx. Similarly, spontaneous release could still be modulated by 5-HT and FMRFa in saline solutions containing 1 mM-Cd2+, which blocked both the voltage-gated Ca2+ channels and the evoked transmitter release. 5. To prevent a rise in intracellular Ca2+, we buffered the concentration of Ca2+ in the presynaptic terminals by injecting into the sensory neurone the Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). The injection of BAPTA blocked evoked transmitter release, suggesting that it acted as an effective buffer of Ca2+ in the terminals. However, spontaneous release could still be observed and was still modulated by 5-HT and FMRFa. This suggests that the modulation of spontaneous release does not require an elevation of intracellular Ca2+. 6. We propose that 5-HT and FMRFa can modulate the rate of spontaneous release directly by mechanisms that do not require changes in the intracellular concentration of Ca2+. These mechanisms might contribute an additional component to the presynaptic inhibition and facilitation of evoked transmitter release.

Action Potentials↗